CHLOROFORM
http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~EdFpQW:1
CHLOROFORM
CASRN: 67-66-3
For other data, click on the Table of Contents
Human Health Effects:
Toxicity Summary:
... The general population is exposed to chloroform
principally in food, drinking-water and indoor air in approximately equivalent
amounts. The estimated intake from outdoor air is considerably less. ... Water
use in homes contributes considerably to levels of chloroform
in indoor air and to total exposure. ... Chloroform
is well absorbed in animals and humans after oral administrations but the
absorption kinetics are dependent upon the vehicle of delivery. ... The primary
factors affecting the absorption kinetics of chloroform
following inhalation are its concentration and species-specific metabolic
capacities. It is readily absorbed through the skin of humans and animals and
significant dermal absorption of chloroform
from water while showering has been demonstrated. Hydration of the skin appears
to accelerate absorption of chloroform.
Chloroform distributes throughout the
whole body. Highest tissue levels are reached in the fat, blood, liver, kidneys,
lungs and nervous system. Distribution is dependent on exposure route;
extrahepatic tissues receive a higher dose from inhaled or dermally absorbed chloroform
than from ingested chloroform.
Placental transfer of chloroform has
been demonstrated in several animal species and humans. Chloroform
is eliminated primarily as exhaled carbon dioxide. Unmetabolized chloroform
is retained longer in fat than in any other tissues. The oxidative
biotransformation of chloroform is
catalyzed by cytochrome P-450 to produce trichloromethanol. Loss of HCl from
trichloromethanol produces phosgene as a reactive intermediate. ... The reaction
of phosgene with tissue proteins is associated with cell damage and death. ...
The liver is the target organ for acute toxicity in rats and several strains of
mice. Liver damage is characterized by early fatty infiltration and balloon
cells, progressing to centrilobular necrosis and then massive necrosis. The
kidney is the target organ in male mice of other more sensitive strains. The
kidney damage starts with hydropic degeneration and progresses to necrosis of
the proximal tubules. ... In mice the oral LD50 values range from 36 to 1366 mg chloroform/kg
body weight, whereas for rats, they range from 450 to 2000 mg chloroform/kg
body weight. ... The carcinogenic effects of chloroform
on the liver and kidney of rodents appear to be closely related to cytotoxic and
cell replicative effects observed in the target organs. ... The weight of the
available evidence indicates that chloroform
has little, if any, capability to induce gene mutation or other types of direct
damage to DNA. ... There are some limited data to suggest that chloroform
is toxic to the fetus but only at doses that are maternally toxic. ... In
humans, anesthesia may result in death due to respiratory and cardiac
arrhythmias and failure. Renal tubular necrosis and renal dysfunction have also
been observed in humans. ... The mean lethal oral dose for an adult is estimated
to be about 45 g, but large interindividual differences in susceptibility occur.
There is some weight of evidence for an association between exposure to
disinfection byproducts in drinking water and colorectal and bladder cancer in
some epidemiological studies. ... The evidence for the carcinogenicity of
chlorinated drinking water in humans is inadequate. In addition, the
disinfection byproducts cannot be attributed to chloroform
per se. ... However, it is cautioned that where local circumstances require that
a choice must be made between meeting microbiological limits or limits for
disinfection byproducts such as chloroform,
the microbiological quality must always take precedence. ... Levels of chloroform
in surface waters are generally low and would not be expected to present a
hazard to aquatic organisms. However, higher levels of chloroform
in surface water resulting from industrial discharges or spills may be hazardous
to the embryo-larval stages of some aquatic species.
Evidence for Carcinogenicity:
CLASSIFICATION: B2; probable human carcinogen.
BASIS FOR CLASSIFICATION: Based on increased incidence of several tumor types in
rats and three strains of mice. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL
CARCINOGENICITY DATA: Sufficient.
Evaluation: There is inadequate evidence in
humans for the carcinogenicity of chloroform.
There is sufficient evidence in experimental animals for the carcinogenicity of chloroform.
Overall evaluation: Chloroform is
possibly carcinogenic to humans (Group 2B).
A3. Confirmed animal carcinogen with unknown
relevance to humans.
Human Toxicity Excerpts:
ACUTE ... RESPONSES FROM EXPOSURE AT VARIOUS
CONCN OF CHLOROFORM IN MAN HAVE BEEN
REPORTED TO BE: FAINTING SENSATION & VOMITING FROM 4096 PPM; DIZZINESS &
SALIVATION AFTER FEW MIN AT 1475 PPM; INCR INTRACRANIAL PRESSURE & NAUSEA IN
7 MIN; AFTER-EFFECTS, FATIGUE & HEADACHE FOR SEVERAL HR FROM 1024 PPM.
RESPONSES ASSOC WITH EXPOSURE TO /CHLOROFORM/
CONCN BELOW ANESTHETIC OR PREANESTHETIC LEVEL ARE TYPICALLY INEBRIATION &
EXCITATION PASSING INTO ... /CNS DEPRESSION/. VOMITING AND GI UPSETS MAY BE
OBSERVED. EXPOSURE INCL RESP DEPRESSION, COMA, RENAL DAMAGE, & LIVER DAMAGE
AS MEASURED BY ELEVATED SERUM ENZYME LEVELS.
SPLASH OF LIQ CHLOROFORM
IN THE EYES CAUSES IMMEDIATE BURNING PAIN, TEARING, & REDDENING OF
CONJUNCTIVA. THE CORNEAL EPITHELIUM IS USUALLY INJURED & MAY BE PARTIALLY
LOST. HOWEVER, REGENERATION IS PROMPT, AND AS A RULE THE EYE RETURNS TO NORMAL
IN 1 TO 3 DAYS.
CHLOROFORM
EXPOSURE HAS REPEATEDLY BEEN FATAL TO MAN. RAPID DEATH WAS ATTRIBUTABLE TO
CARDIAC ARREST & DELAYED DEATH TO LIVER & KIDNEY DAMAGE. SYMPTOMS OF CHLOROFORM
EXPOSURE INCL RESP DEPRESSION, COMA, RENAL DAMAGE, & LIVER DAMAGE AS
MEASURED BY ELEVATED SERUM ENZYME LEVELS.
CHLOROFORM
WITH METABOLIC ACTIVATION FAILED TO INDUCE CHROMOSOME BREAKAGE OR SISTER-CHROMATID
EXCHANGES IN HUMAN LYMPHOCYTES.
... Twenty-five percent of 68 workers handling
chloroform in a chemical plant had
enlarged livers. The lengths of employment were between 1 and 4 yr. Concn of chloroform
in air ranged from 10-200 ppm.
33-year-old male who habitually inhaled chloroform
for 12 yr, had psychiatric and neurologic symptoms of depression, loss of
appetite, hallucination, ataxia, and dysarthria. Other symptoms from habitual
use are moodiness, mental and physical sluggishness, nausea, rheumatic pain, and
delirium.
Signs of chloroform
poisoning in humans include a characteristic sweetish odor on the breath,
dilated pupils, cold and clammy skin, initial excitation alternating with
apathy, loss of sensation, abolition of motor functions, prostration,
unconsciousness and eventual death.
Worker exposure to concn of chloroform
of over 112 mg/cu m have been reported to result in depression, ataxia,
flatulence, irritability, and liver and kidney damage.
Toxic blood level: 70.0 to 250 mg/l; Lethal
blood level: 390.0 mg/l.
An increased incidence of cardiac arrhythmias
has been demonstrated during surgery in patients anesthetized with chloroform
as compared with other anesthetic agents at vapor concn of 22,500 ppm.
... Produces CNS depression ... Can sensitive
the heart to arrhythmias produced by catecholamines. The hepatotoxic potential
is highest with chloroform ...
Fatal doses of liquid anesthetic agents by
ingestion or inhalation are approx as follows: ... chloroform,
10 ml ... .
Concentrations /of chloroform/
up to about 400 ppm can be endured for 30 min without complaint; 1000 ppm
exposure for 7 min can cause dizziness and GI upset; 14,000 ppm can cause /CNS
depression/.
/Chloroform
causes/ local irritation (hyperemia, erythema, moisture loss) at the site of
skin absorption.
Both di- and tri-halogenated methane
derivatives have been found to produce increased blood levels of methemoglobin;
the greatest increase caused by iodo-, followed by bromo- and chloro- compounds.
CNS functional disturbances are reported, including depression of rapid
eyemovement sleep, as seen in carbon monoxide exposures. /Di- and tri-halogenated
methane derivatives/
Skin, Eye and Respiratory Irritations:
Skin and eye irritant
Threshold of irritation: 20480 mg/cu m
Drug Warnings:
Maternal Medication usually Compatible with
Breast-Feeding: Chloroform: Reported
Sign or Symptom in Infant or Effect on Lactation: None. /from Table 6/
Medical Surveillance:
Initial Medical Examination: A complete
history and physical examination ... to detect pre-existing conditions that
might place the exposed employee at increased risk, and to establish a baseline
for future health monitoring. Examination of liver, kidneys, and heart should be
stressed. The skin should be examined for evidence of chronic disorders. A
profile of liver function should be obtained by using a medically acceptable
array of biochemical tests. Since kidney damage has also been observed from
exposure /to chloroform/, a urinalysis
should be obtained to include at a minimum: specific gravity, albumin, glucose,
and a microscopic /examination of/ centrifuged sediment. Periodic Medical
Examination: The aforementioned medical examinations should be repeated on an
annual basis.
PRECAUTIONS FOR "CARCINOGENS":
Whenever medical surveillance is indicated, in particular when exposure to a
carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic
and/or other/ tests that might become useful or mandatory. /Chemical
Carcinogens/
Populations at Special Risk:
... Individuals with diseases of liver,
kidneys, and CNS.
A history of, or physical signs consistent
with, chronic alcoholism probably constitutes an increased risk for employees
exposed to chloroform.
Probable Routes of Human Exposure:
Shell Chem Co, Rocky Mountain Arsenal - mean
TWA were 2.6, 0.4 and 0.2 ppm for production operaters, drummers/bottle fillers
and maintenance/utility personnel (pesticide plant)(1). Polish pharmaceutical
plant 2 - 205 ppm(1); police forensic lab - 8 hr TWA - 15.8 ppm (range 2.6-46.4
ppm)(1); film manufacturing plant using a solvent containing 22% chloroform
1968-72 - 7-170 ppm (mean 47 ppm, 79 samples)(1).
NIOSH (NOES Survey 1981-1983) has
statistically estimated that 95,773 workers (41,397 of these are female) are
potentially exposed to chloroform in
the US(1). Occupational exposure to chloroform
may occur through inhalation and dermal contact with this compound at workplaces
where chloroform is produced or
used(SRC). The general population may be exposed to chloroform
via inhalation of ambient air(2,3), ingestion of food(2) and drinking
water(2,4).
Personal air concns of chloroform
were studied for 12 hr exposure periods(1). Forty eight people in New Jersey
during Feb 1983 had a mean personal exposure of 4.0 ug/cu m during day and
nighttime while 40 individuals in Los Angeles, CA during June 1987 had a mean
personal exposure of 3.8 ug/cu m during the day and 0.92 ug/cu m during
nighttime(1). In Antioch-Pittsburg, CA during June 1984, 68 people had a mean
personal exposure to chloroform of
0.47 ug/cu m during the day and 0.80 during nighttime(1). Several studies of
indoor swimming pools indicate that inhalation can provide substantial amounts
of chloroform(1). A study of 3 indoor
swimming pools and 3 life guards resulted in increases of personal air exposures
to chloroform(1). Personal air
exposures for the 3 lifeguards at the indoor pool were 95, 68, and 46 ug/cu m
while at home exposures dropped to 2.2, 2.0 and 5.2 ug/cu m(1). However, outdoor
pools showed no difference in personal air exposure to chloroform(1).
A pilot study carried out in Japan measured the intake of chloroform
from air, food, and tap water for 7 Japanese housewives on 3 consecutive days in
each of two seasons. For all 7 subjects in winter and 6 out of the 7 in summer,
food contributed the most to their daily intake, accounting for about half of
the daily intake of 37 ug in the summer and 70% of the smaller winter intake of
14 ug(1).
Several experiments indicate that dermal
absorption of chloroform during a
shower is roughly equivalent to inhalation exposure during the shower(1). It has
been estimated that about half the exposure from a 10-min shower is due to
dermal absorption(1). The major source of exposure to chloroform
is chlorination of water supplies(1). The results in exposure through ingestion
of drinking water, but also through inhalation and skin absorption as a result
of the myriad other uses of chlorinated water in the home: showers, baths,
washing clothes and dishes, etc supports this(1). At a typical personal exposure
to chloroform of about 3 ug/cu m(not
including exposure during the shower), this results in an estimated intake of
about 24 ug/day for women and 30 ug/day for men(1). A typical chloroform
level in soft drinks is about 23 ug/l(1). For an avg soft drink intake of 289
ml/day, this corresponds to a chloroform
intake of about 6 ug/day(1). Limited data on levels of trihalomethanes
(including chloroform) in food suggest
that the additional intake from other foods and dairy products will be small(1).
Thus, total intake from food and beverages appears to be approximately 10 ug/day
for someone who drinks an avg amount of soft drinks(1).
Body Burden:
Old Love Canal, Niagara Falls, NY - 9
individuals: breath 3.9-95 ug/cu m, 26 ug/cu m median; blood 1.1-3.0 ng/ml, 1.6
ng/ml median; urine 460-1500 ng/l, 860 ng/l median(1). England - 8 individuals:
body fat 5-68 ppb; var organs 1-10 ppb(2); US - 4 urban sites: mothers' milk 7
of 8 samples pos, detected, not quantified(3).
The largest existing data set on chloroform
concns in the body has been provided by the TEAM Study measurements of exhaled
breath(1). About 800 people provided more than 1250 breath samples with mean
concns generally in the range of 0.5-3 ug/cu m with generally lower levels in
California compared with other sites (New Jersey, Maryland, North Dakota, and
North Carolina)(1). In a study of 163 people at indoor swimming pools, exposed
individuals had a mean chloroform
concn in the higher alveolar of 83 ug/cu m(1). Breath exposures were also
studied from a single subject who swam for 30 mins on 3 occasions, rested in the
water for the same length of time on one occasion and stayed near the pool but
out of the water for 30 mins on the final occasion(1). Pre-exposure breath
concns were less than 2 ug/cu m on all occasions, rising to 15 to 25 ug/cu m 2.5
mins after completing the swimming periods, but only to 11 mg/cu m after the
poolside exposure period(1). A study of chloroform
found in blood revealed that out of 979 people sampled between 1988-1992, the
mean chloroform concn was 0.0444 ng/ml(1).
This suggests that a large percentage of the U.S. population is exposed to chloroform,
but that very large exposures are rare(1). Chloroform
was also detected in 40 out of 42 breast milk samples at levels ranging from 0.1
to 65 ng/ml from nursing mothers in two New Jersey hospitals and from three
other hospitals in Pennsylvania, Louisiana, and West Virginia(1).
Average Daily Intake:
... Although data are scarce, maximum exposure
/to chloroform/ due to ingestion of
food has been estimated at 0.04 mg/day.
Animal Toxicity Studies:
Toxicity Summary:
... The general population is exposed to chloroform
principally in food, drinking-water and indoor air in approximately equivalent
amounts. The estimated intake from outdoor air is considerably less. ... Water
use in homes contributes considerably to levels of chloroform
in indoor air and to total exposure. ... Chloroform
is well absorbed in animals and humans after oral administrations but the
absorption kinetics are dependent upon the vehicle of delivery. ... The primary
factors affecting the absorption kinetics of chloroform
following inhalation are its concentration and species-specific metabolic
capacities. It is readily absorbed through the skin of humans and animals and
significant dermal absorption of chloroform
from water while showering has been demonstrated. Hydration of the skin appears
to accelerate absorption of chloroform.
Chloroform distributes throughout the
whole body. Highest tissue levels are reached in the fat, blood, liver, kidneys,
lungs and nervous system. Distribution is dependent on exposure route;
extrahepatic tissues receive a higher dose from inhaled or dermally absorbed chloroform
than from ingested chloroform.
Placental transfer of chloroform has
been demonstrated in several animal species and humans. Chloroform
is eliminated primarily as exhaled carbon dioxide. Unmetabolized chloroform
is retained longer in fat than in any other tissues. The oxidative
biotransformation of chloroform is
catalyzed by cytochrome P-450 to produce trichloromethanol. Loss of HCl from
trichloromethanol produces phosgene as a reactive intermediate. ... The reaction
of phosgene with tissue proteins is associated with cell damage and death. ...
The liver is the target organ for acute toxicity in rats and several strains of
mice. Liver damage is characterized by early fatty infiltration and balloon
cells, progressing to centrilobular necrosis and then massive necrosis. The
kidney is the target organ in male mice of other more sensitive strains. The
kidney damage starts with hydropic degeneration and progresses to necrosis of
the proximal tubules. ... In mice the oral LD50 values range from 36 to 1366 mg chloroform/kg
body weight, whereas for rats, they range from 450 to 2000 mg chloroform/kg
body weight. ... The carcinogenic effects of chloroform
on the liver and kidney of rodents appear to be closely related to cytotoxic and
cell replicative effects observed in the target organs. ... The weight of the
available evidence indicates that chloroform
has little, if any, capability to induce gene mutation or other types of direct
damage to DNA. ... There are some limited data to suggest that chloroform
is toxic to the fetus but only at doses that are maternally toxic. ... In
humans, anesthesia may result in death due to respiratory and cardiac
arrhythmias and failure. Renal tubular necrosis and renal dysfunction have also
been observed in humans. ... The mean lethal oral dose for an adult is estimated
to be about 45 g, but large interindividual differences in susceptibility occur.
There is some weight of evidence for an association between exposure to
disinfection byproducts in drinking water and colorectal and bladder cancer in
some epidemiological studies. ... The evidence for the carcinogenicity of
chlorinated drinking water in humans is inadequate. In addition, the
disinfection byproducts cannot be attributed to chloroform
per se. ... However, it is cautioned that where local circumstances require that
a choice must be made between meeting microbiological limits or limits for
disinfection byproducts such as chloroform,
the microbiological quality must always take precedence. ... Levels of chloroform
in surface waters are generally low and would not be expected to present a
hazard to aquatic organisms. However, higher levels of chloroform
in surface water resulting from industrial discharges or spills may be hazardous
to the embryo-larval stages of some aquatic species.
Evidence for Carcinogenicity:
CLASSIFICATION: B2; probable human carcinogen.
BASIS FOR CLASSIFICATION: Based on increased incidence of several tumor types in
rats and three strains of mice. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL
CARCINOGENICITY DATA: Sufficient.
Evaluation: There is inadequate evidence in
humans for the carcinogenicity of chloroform.
There is sufficient evidence in experimental animals for the carcinogenicity of chloroform.
Overall evaluation: Chloroform is
possibly carcinogenic to humans (Group 2B).
A3. Confirmed animal carcinogen with unknown
relevance to humans.
Non-Human Toxicity Excerpts:
MICE EXPOSED TO 8,000 PPM OF CHLOROFORM
DIED AFTER 3 HR OF EXPOSURE, RABBITS DIED AFTER A 2-HR EXPOSURE TO 12,500 PPM
... DOGS SURVIVED MUCH HIGHER CONCN. ACUTE CHLOROFORM
EXPOSURE MAY RESULT IN DEATH BY RESP ARREST. PRIMARY TOXIC RESPONSE AT LOWER
LEVELS OF EXPOSURE IS HEPATOTOXICITY LEADING TO FATTY LIVER & CENTRILOBULAR
NECROSIS.
... 40% INHIBITION OF MICROSOMAL
DRUG-METABOLIZING ENZYME ACTIVITY IN RATS FED 1.05 ML/KG OF CHLOROFORM
24 HR PRIOR TO SACRIFICE /IS REPORTED/. THIS MAY BE RELATED TO DEGREE OF HEPATIC
NECROSIS PRODUCED BY CHLOROFORM OR TO
MORE SUBTLE EFFECT ON MICROSOMAL ENZYME SYSTEM.
GROUPS OF 5 STRAIN A MICE OF EACH SEX, 3 MO
OLD AT THE BEGINING OF THE EXPERIMENT WERE GIVEN 30 ORAL DOSES OF 0.1, 0.2, 0.4,
0.8 OR 1.6 ML/KG (0.15-2.4 G/KG BODY WT) CHLOROFORM
IN OLIVE OIL AT 4-DAY INTERVALS. SURVIVORS WERE KILLED 1 MO AFTER LAST
TREATMENT. ALL FEMALES AT THE 3 HIGHEST DOSES AND ALL MALES AT THE 3 HIGHEST
DOSES DIED EARLY IN THE EXPERIMENT. NONMETASTASIZING HEPATOMAS & CIRRHOSIS
WERE FOUND IN ALL SURVIVING FEMALES GIVEN 0.8 OR 0.4 ML/KG BODY WEIGHT PER DOSE.
NO HEPATOMAS WERE OBSERVED IN THOSE AT THE TWO LOWEST DOSE LEVELS OR IN THE
CONTROLS.
GROUPS OF 50 MALE & 50 FEMALE B6C3F1 MICE,
5 WK OF AGE, RECEIVED 2-5% SOLN OF CHLOROFORM
(USP GRADE) IN CORN OIL BY GAVAGE 5 TIMES/WK FOR 78 WK. THE INITIAL DOSE LEVELS
FOR MALES WERE 100 AND 200 MG/KG BODY WT, AND THOSE FOR FEMALES 200 AND 400
MG/KG BODY WT. THESE DOSES WERE INCREASED AFTER 18 WEEKS TO 150 AND 300 MG/KG
BODY WT FOR MALES AND 250 AND 500 MG/KG BODY WT FOR FEMALES, SO THAT THE AVERAGE
LEVELS WERE 138 AND 277 MG/KG BODY WT FOR MALES AND 238 AND 477 MG/KG BODY WT
FOR FEMALES. POOLED CONTROL GROUPS, CONSISTING OF 77 MALE AND 80 FEMALE MICE,
AND MATCHED CONTROL GROUPS, CONSISTING OF 20 MALES AND 20 FEMALES, WERE TREATED
WITH CORN OIL ONLY. THE EXPERIMENT WAS TERMINATED AT 92-93 WEEKS. THE INCIDENCE
OF HEPATOCELLULAR CARCINOMAS IN ALL TREATED GROUPS OF MICE WAS STATISTICALLY
SIGNIFICANT (P < 0.0001) WHEN COMPARED WITH THAT IN CONTROLS.
GROUPS OF 50 MALE & 50 FEMALE
OSBORNE-MENDEL RATS, 52 DAYS OLD, RECEIVED A 10% SOLUTION OF CHLOROFORM
(USP GRADE) IN CORN OIL BY GAVAGE 5 TIMES WEEKLY. MALES WERE GIVEN DOSES OF 90
AND 180 MG/KG BODY WT FOR 78 WEEKS; FEMALE RATS STARTED ON DOSE LEVELS OF 125
AND 250 MG/KG BODY WT, BUT THESE WERE LOWERED TO 90 AND 180 MG/KG BODY WT AFTER
22 WEEKS, GIVING AN AVERAGE LEVEL OF 100 AND 200 MG/KG BODY WT FOR THE STUDY.
POOLED CONTROL GROUPS OF 100 MALES AND 100 FEMALES AND MATCHED CONTROL GROUPS OF
20 MALES AND 20 FEMALES WERE TREATED WITH THE VEHICLE ONLY. THE EXPERIMENT WAS
TERMINATED AT 111 WEEKS. THE INCIDENCE OF KIDNEY EPITHELIAL TUMOURS IN MALE RATS
WAS STATISTICALLY GREATER (P= 0.0016) THAN THAT IN CONTROLS.
RATS WERE EXPOSED TO SUBANESTHETIC DOSES OF CHLOROFORM:
150, 500 & 1500 MG/CU M (30, 100 & 300 PPM), IN AIR BY INHALATION FOR 7
HR/DAY ON DAYS 6-15 OF GESTATION. 100 PPM DOSE CAUSED LOW INCIDENCE OF ACAUDATE
FETUSES WITH IMPERFORATED ANUSES. ALL DOSES OF CHLOROFORM
WERE FETOTOXIC & RETARDED DEVELOPMENT.
CLINICAL SIGNS OBSERVED IN RATS FOLLOWING
SINGLE ORAL DOSES OF CHLOROFORM WERE
SEDATION, FLACCID MUSCLE TONE, ATAXIA, PILOERECTION, & PROSTRATION. MALES
WERE MORE SUSCEPTIBLE THAN FEMALES.
MALE & FEMALE MICE WERE GAVAGED WITH
VEHICLE OR CHLOROFORM 31.1 MG/KG/DAY
FOR 21 DAYS PRIOR TO MATING, THROUGHOUT MATING & DAMS THROUGHOUT GESTATION
& LACTATION. PUPS GAVAGED WITH SAME DOSE DAILY BEGINNING ON DAY 7. NO
DIFFERENCES IN CONTROL & TREATED MICE.
CELLS OF SACCHAROMYCES CEREVISIAE, HARVESTED
FROM LOG-PHASE CULTURES, CONTAIN CYTOCHROME P450 & ARE CAPABLE OF METAB
PROMUTAGENS TO GENETICALLY ACTIVE PRODUCTS. THE ACTIVITIES OF 7 HALOGENATED
ALIPHATIC HYDROCARBONS IN THE YEAST SYSTEM WERE INVESTIGATED. CHLOROFORM
INDUCED MITOTIC GENE CONVERTANTS & RECOMBINANTS &, TO A LESSER EXTENT,
GENE REVERTANTS WHEN INCUBATED WITH LOG-PHASE CELLS OF YEAST STRAIN D7. CHLOROFORM
CONCN USED RANGED FROM 21 TO 54 MM.
THE TOXIC EFFECTS OF A SINGLE ORAL DOSE OF CHLOROFORM
WERE EVALUATED IN C57BL, DBA, AND F1 MALE MICE. SOLN OF CHLOROFORM
IN PEANUT OIL (FINAL VOL= 0.1 ML/10 G BODY WT) WERE ADMIN ONCE BY GAVAGE TO
9-WK-OLD MICE. DBA/2J MALE MICE ARE MORE SENSITIVE TO THE 10-DAY LETHAL EFFECT
OF CHLOROFORM THAN ARE C57BL/6J MALES,
WHEREAS B6D2F1/J ARE INTERMEDIATE. THIS RELATIVE ORDER OF SENSITIVITY IS
PRESERVED FOLLOWING SUBLETHAL DOSES IN REGARD TO RADIOLABEL ACCUMULATION INTO
SUBCELLULAR BIOCHEMICAL FRACTIONS AND RENAL, BUT NOT HEPATIC, DYSFUNCTION.
KIDNEYS FROM MICE OF ALL THREE GENOTYPES ARE ABLE TO REPAIR TUBULAR DAMAGE FROM CHLOROFORM.
CHLOROFORM
WAS NEGATIVE IN THE SPERM MORPHOLOGY ASSAY WHEN ADMIN TO GROUPS OF 5 (CBAXBALB/C)F1
MALE MICE IP 5 TIMES/DAY @ 5.0 ML/KG/DAY.
EPIDIDYMAL SPERMATOZOA OF (C57BL/C3H)F1 MICE
SHOWED SIGNIFICANT INCREASES IN ABNORMALITIES AFTER /28 DAYS OF/ EXPOSURE TO CHLOROFORM
/NEAR 0.1 MAC AND GREATER CONCN/ 4 HR/DAY FOR 5 DAYS.
MICE WERE GIVEN ACCESS TO DEIONIZED WATER FOR
30 MIN DAILY. WHEN FLUID CONSUMPTION STABILIZED, THEY WERE GIVEN 30 MIN ACCESS
TO 0.3% SACCHARIN FOLLOWED BY ORAL DOSES OF 3, 10 OR 30 MG/KG CHLOROFORM
OR VEHICLE (EMULPHOR). BEGINNING 24 HR LATER SUBJECTS WERE GIVEN 2-BOTTLE CHOICE
TEST SACCHARIN VS WATER FOLLOWED BY ADMIN OF CHLOROFORM.
30 MG/KG PRODUCED TASTE AVERSION ON 1ST CHOICE TEST & REDUCTION OF TOTAL
FLUID INTAKE. DOSES OF 3 & 10 MG/KG OR VEHICLE DID NOT AFFECT EITHER
MEASURE. ALSO IT PRODUCED TASTE AVERSIONS WHEN GIVEN AT RELATIVELY LOW DOSES BY
IP ROUTE.
NO EVIDENCE OF POTENTIAL MUTAGENICITY WAS
OBSERVED WHEN TESTED IN 5 STRAINS OF SALMONELLA TYPHIMURIUM WITH & WITHOUT
S-9 MICROSOMAL-ENZYME PREPN. S-9 PREPN WAS DERIVED FROM LIVERS & KIDNEYS OF
RATS & MICE PREVIOUSLY EXPOSED TO AROCLOR 1254.
In mice, immature males, castrated adult
males, and estrogen treated males were resistant to chloroform
renal toxicity, whereas mature males and testosterone treated females were
sensitive.
Rabbits developed slight hyperemia with
moderate necrosis and scar tissue formation following one to two, 24 hr dermal
applications of chloroform on shaven
skin.
Cultured Chinese hamster fibroblasts when
exposed to 1-2.5% chloroform did not
demonstrate mutagenic changes. However, fibroblast multiplication rate was
depressed in a dose-dependent pattern.
/Chloroform/
did not induce sister chromatid exchanges in Chinese hamster ovary cells when
tested at 0.71% vol/vol.
Exposure to chloroform
for 1-5 min caused a gradual browning of the surfaces of Phaseolus vulgaris
cotyledons during subsequent incubation for 10-72 hr; this was accompanied by
isoflavanoid accumulation in the cotyledons. ... The amts of phytoalexin
produced increased with increasing damage, phaseollin, phaseollinisoflavan, and
kievitone (< or = to 96 ug/g cotyledon). ... Cotyledons treated with chloroform
for > 10 min became entirely flaccid and did not become pigmented or produce
any of the above compounds. No isoflavanoids were detected in undamaged
cotyledons. Hence, accumulation of phytoalexins may be a direct consequence of
the death of superficial cells of the bean cotyledons.
40 and 160 ppm /chloroform/
caused no mortality in goldfish after 4 days while at 300 ppm a 30% mortality
was observed. 40 ppm caused no mortality in guppies while at 160 and 300 ppm, 30
and 50% mortality, respectively, was observed. At 160 and 300 ppm the fish
acquired darker pigmentation, retarded reproduction rate and growth, and caused
an equilibrium loss (especially at 300 ppm). 40 ppm caused five-fold incr in
leukocytes after a six month exposure.
The effects of lifetime exposure to chloroform
... were studied in Wistar rats. ... Treatment was initiated with weanlings at 2
ml chlorofrom per liter of water. Concentrations were halved at 72 weeks because
of increasing water intake among the test animals. ... Treated rats weighed less
than unexposed controls at all ages. At about 15 to 17 weeks, females had a high
consumption of water and ... /chloroform/
than males. The incidence of neoplastic nodules was significantly increased in
females. ... /Both/ males /and females/ treated with chlorofrom had a high
incidence of hepatic adenofibrosis.
Characteristics of chloroform
(CHCl3) nephrotoxicity and of 2-hexanone potentiation were evaluated in adult
male Fischer 344 rats pretreated with vehicle (oil, 10 ml/kg, po) or 2-hexanone
(10 mmol/kg, po) 18 hr prior to chloroform
exposure. ... Little metabolism of (14)C-chloroform
by renal cortical microsomes from vehicle or 2-hexanone pretreated rats was
detected. However, chloroform produced
a concn-related dysfunction when added to renal cortical slices from Fischer 344
or Sprague-Dawley rats. The degree of chloroform
toxicity in vitro was not altered when renal cortical slices were preincubated
with chloroform (8.5 microliter) under
an atmosphere of carbon monoxide. In renal cortical slices, deuterated-chloroform
was less toxic than chloroform.
Although 2-hexanone pretreatment increased renal slice metabolism of (14)C-chloroform
twofold, this incr was not associated with an incr in nephrotoxicity after
direct exposure of slices to chloroform
(0 to 10 microliter) in vitro. Chloroform
(0.5 ml/kg, ip) did not alter renal cortical glutathione concn in vehicle or
2-hexanone pretreated rats. The association of (14)C-chloroform-derived
radiolabel was incr over control by 2-hexanone pretreatment in protein, lipid,
and acid soluble fractions from the renal cortex by approx two-, two-, and
five-fold, respectively. In conclusion, renal cytochrome p450 did not appear to
mediate chloroform metabolism and
nephrotoxicity in the rat to the extent observed previously in mice. 2-Hexanone
appeared to potentiate nephrotoxicity by a mechanism different than that
observed in rat liver.
The genetic damage caused by ... chloroform
... was studied in rodents (Rattus norvegicus and Mus musculus). ... Aneuploidy,
stages of fuzziness, despiralization and stickiness of the chromosomes were
observed. Some metaphases with gaps, breaks and translocations, were also
encountered.
The carcinogenic activity of chloroform
administered at 0, 200, 400, 900, and 1800 mg/l in drinking water was studied in
male Osborne-Mendel rats and female B6C3F1 mice. A second control group was
included in the study and was restricted to the water consumption of the
high-dose group. Animals were maintained on study for 104 weeks. ... Chloroform
increased the yield of renal tubular adenomas and adenocarcinomas in male rats
in a dose-related manner. For the high-dose group, which corresponded to a
time-weighted average dose of 160 mg/kg per day for 104 weeks, there was a 14%
incidence of renal tubular adenomas and adenocarcinomas, vs 1% in the control
group. This compares to a 24% incidence observed when 180 mg/kg per day of chloroform
was administered for 78 weeks in earlier studies. In contrast, chloroform
in the drinking water of mice failed to increase the incidence of hepatocellular
carcinomas in female B6C3F1 mice. The highest dose group received a
time-weighted average dose of 263 mg/kg per day for 104 weeks, resulting in a 5%
combined incidence of hepatocellular adenomas and carcinomas relative to a 6%
incidence in the control groups. In a prior National Cancer Institute study an
80% incidence of hepatocellular carcinomas was observed at 270 mg/kg per day for
78 weeks. Chloroform administered in
drinking water evidently is capable of inducing cancer in the rat kidney.
However, the lack of response in the mouse liver when chloroform
is supplied in the drinking water suggests that earlier reports of chloroform
hepatocarcinogenesis may be related to some interaction with the mode of
administration (corn oil gavage).
The acute toxicity of chloroform
in experimental animals is species-, strain-, sex- and age-dependent.
Pregnant C57B1 mice were administered chloroform,
(14)C-chloroform, by inhalation on
days 11, 14, and 17 of gestation. In another experiment, six 4-day-old mice
received an ip dose of 2 uCi of (14)C-chloroform
dissolved in maize oil. The pregnant mice and the exposed newborns were killed
for autoradiography studies. A high uptake of (14)C-chloroform
was noted in the pregnant mice after inhalation, especially in the respiratory
epithelium, liver, fat, lung, brain, and renal cortex. Metabolites of chloroform
accumulated in the amniotic fluid. In the newborn mice, a notable accumulation
of chloroform was noted in the
respiratory epithelium, oral/esophageal mucosa, liver, salivary glands, and the
conjunctiva of the eye.
... Male and female B6C3F1 mice were
administered chloroform at 60, 130,
and 270 mg/kg per day for 90 days. At sacrifice, body and organ weights were
measured, and blood was recovered to perform the following serum chemistry
measurements (in order of priority): glutamate oxalacetate transaminase, lactate
dehydrogenase, blood urea nitrogen and triglyceride levels. The liver was
sectioned for histopathological examination. Chloroform
increased glutamate oxalacetate transaminase levels significantly only when
administered in corn oil at a dose of 270 mg/kg in both male and female mice. It
had no effect on lactate dehydrogenase (LDH) activity. There was a small
increase in BUN when chloroform was
administered in corn oil, but not when adminsitered in 2% Emulphor. When
administered in corn oil, chloroform
significantly decreased serum triglyceride levels but was without effect on this
parameter when administered in 2% Emulphor. Chloroform
decreased body weight and increased liver weight with both vehicles, but the
effects were significantly greater when it was administered in corn oil.
In C57 male black mice, renal tubular necrosis
was produced by ip admin of 300 mg of chloroform/kg;
an ip injection of 445 mg/kg caused necrosis in the liver and the kidneys.
NCI strain A mice, receiving chloroform
repeatedly (30 doses by stomach tube at 4-day intervals) developed hepatomas.
... Hepatomas and cirrhosis of the liver were induced only if the dosage was
large enough to produce necrosis of the liver (individual doses greater than 300
mg/kg).
... Negative results of /chloroform/
carcinogenicity were obtained in beagle dogs after 7.5 yr, in Sprague-Dawley
rats, and in 3 of 4 strains of mice. In the fourth strain (ICI Swiss), renal
tumors occurred only in males at the 60 mg/kg/day dose, but not at the 17 mg
dose. In the male mouse CBA strain, survival was better than in controls, and
fewer liver tumors were seen in the treated than the control mice. The lack of
toxicity was attributed to the small doses used in these studies (15 and 30
mg/kg/day, dogs; 60 mg/kg/day in mice and rats). The hepatocellular degeneration
and necrosis and the abdominal distention ... were induced by several times
higher dosage.
... The hepatotoxic effect of chloroform
is 20 times greater than the hepatotoxic effect of trichloroethylene and 10
times greater than that of tetrachloroethylene.
Two studies in rats exposed repeatedly to chloroform
/conclude that/ ... 25-30 ppm, 7 hr/day, 5 days/wk for 6 mo does not produce
organ injury; liver and kidney injury start to appear at 50 ppm exposure; and
the severity of the injury is concentration dependent. Data ... also indicates
that rats are more sensitive to chloroform
than other species (mice, rabbits, guinea pigs, dogs).
Chloroform
0.1 to 0.5% was an effective bactericide against small inocula of Staphylococcus
aureus, Escherichia coli, and Pseudomonas aeruginosa; against large inocula chloroform
0.1% was effective against Pseudomonas aeruginosa, but higher concn were needed
against the other organisms. Spores of Bacillus pumilus were not killed.
... Abnormal mitosis has occurred in /plant/
cells exposed to chloroform concn of
0.025%. Toxic effects also occur at this level. Concn greater than 0.25% have
been shown to be lethal.
... Rabbits, rats, guinea pigs, and dogs /were
exposed/ to 25, 50, or 85 ppm chloroform,
7 hr/day, 5 days/wk for six months. Histopathological evaluation of animals
indicated centrilobular necrosis and cloudy swelling of the kidneys. The effects
of the 25 ppm dose were characterized as mild and reversible.
ANESTHESIA WITH DEUTERATED CHLOROFORM
AT 0.36% PRODUCED A 35% DECR IN SERUM GLUTAMIC PYRUVIC TRANSAMINASE IN RATS.
THUS, DEUTERATION OF VOLATILE ANESTHETICS CHANGES THEIR METABOLISM, IN MOST
CASES PRODUCING DECR IN METABOLISM. THIS MAY LESSEN ORGAN TOXICITY.
... Rats pretreated with phenobarbital, but
not untreated rats, will produce conjugated dienes during chloroform
anesthesia; depression of glucose-6-phosphatase activity also occurs after chloroform
only in phenobarbital-pretreated rats. ... Since chloroform-induced
liver injury is more severe in phenobarbital-pretreated rats, the possibility
exists that the initial lesion induced by chloroform
in these animals is only aggravated by the appearance of lipid peroxidation.
These findings cast doubt on the general applicability of lipid peroxidation as
a mechanism for necrogenic haloalkanes.
STUDIES WERE DONE USING MALE B6C3F1 MICE TO
INVESTIGATE POTENTIAL OF CHLOROFORM TO
INDUCE GENETIC DAMAGE &/OR ORGAN TOXICITY AT SITES WHERE TUMORS HAVE BEEN
OBSERVED IN VARIOUS BIOASSAYS. THEY REVEALED THAT CARCINOGENIC DOSES PRODUCED
SEVERE NECROSIS AT SITES WHERE TUMORS DEVELOPED. NONCARCINOGENIC DOSES FAILED TO
INDUCE THIS RESPONSE. STUDIES OF DNA ALKYLATION & DNA REPAIR IN VIVO FAILED
TO GIVE ANY INDICATION THAT IT HAD PRODUCED GENETIC ALTERATIONS ASSOC WITH KNOWN
GENOTOXIC CHEMICALS. DATA SUGGEST THAT PRIMARY MECHANISM OF CHLOROFORM-INDUCED
CARCINOGENESIS IS NONGENETIC.
RELATIONSHIP BETWEEN ACUTE TOXICITY FROM ORAL
ADMIN & LONG-TERM TUMORIGENIC POTENTIAL WAS STUDIED IN MALE CFLP OUTBRED
SWISS ALBINO MOUSE STRAIN. SINGLE DOSE OF CHLOROFORM,
APPROX 18 MG/KG HAD NO DETECTABLE ACUTE TOXIC EFFECT ON LIVER OR KIDNEYS &
DID NOT STIMULATE REGENERATIVE ACTIVITY. TOXICITY & TISSUE REGENERATION WERE
OBSERVED WITH SINGLE 60 MG/KG OR HIGHER DOSE. IN EARLIER LONG-TERM STUDIES IN
MICE OF SAME STRAIN, KIDNEY TUMORS OCCURRED IN MALES GIVEN 60 MG/KG/DAY
THROUGHOUT LIFE BUT NOT IN MICE GIVEN 17 MG/KG/DAY. FINDINGS ARE CONSISTENT WITH
HYPOTHESIS THAT EARLY ACUTE TOXIC CHANGE & SUBSEQUENT REPAIR ARE ESSENTIAL
FOR TUMORIGENESIS IN KIDNEY & LIVER.
CHLOROFORM
INDUCED DOSE-DEPENDENT INCR OF HEPATIC ORNITHINE DECARBOXYLASE AT 100 MG/KG BODY
WT IN FISCHER 344 RATS. FEMALES WERE 2 TO 4 TIMES MORE SUSCEPTIBLE THAN MALES.
NUCLEAR RNA POLYMERASE I ACTIVITY WAS ALSO INDUCED. IT REDUCED RENAL ORNITHINE
DECARBOXYLASE BY 35% RATHER THAN INCREASING IT. INDUCTION OF HEPATIC ORNITHINE
DECARBOXYLASE ACTIVITY MIGHT BE ASSOC WITH REGENERATIVE HYPERPLASIA.
RATS WERE DOSED 1, 5, OR 10 TIMES WITH CHLOROFORM
(0.5 TO 50 MG/KG) AND THE LIVER ENZYME ACTIVITIES DETERMINED. CHLOROFORM
INDUCED CHANGES IN THE 24 ENZYMES INVESTIGATED BUT CAUSED ONLY MINIMAL LIVER
ENLARGEMENT. THE MAIN ENZYMATIC CHANGES WERE: STIMULATION OF GLYCOLYSIS &
OXIDATIVE PHOSPHORYLATION, INCR BREAKDOWN OF PROTEIN & NUCLEIC ACIDS,
REDUCED HEXOSE PHOSPHATE SHUNT ACTIVITY LEADING TO A SHORTAGE OF NADPH IN THE
CELL, AND STIMULATION OF ADRENAL MEDULLARY & CORTICAL SECRETION. SOME OF THE
CHANGES ARE SIMILAR TO THOSE SEEN WITH LARGER AND ANESTHETIC DOSES.
Hepatocytes isolated from male Sprague-Dawley
rats (Harlan, 200-275 g) were exposed to halogenated hydrocarbons including chloroform.
Cell suspensions contained 2-3X10+6 cells/ml and were viable for 6 hr as
indicated by a < 10% increment in the fractional release of aspartate
aminotransferase (AST) activity. The addition of chloroform
(20 mM) caused a rapid release of AST into the incubation medium. The release
peaked within 20 min and approximately 20% (n= 4) of the total activity was
found in the medium. Only 3% of the activity was in the medium of control cells.
Untreated cells or cells treated with vehicle did not exhibit an increase of AST
release with time. The amount of AST release was concentration dependent (tested
at 10 and 20 mM) and related to the oil/water partition coefficient. Cellular
oxygen consumption was reduced by approximately 50% (n= 8) by 20 mM chloroform,
and the reduction was dose dependent. The effects of cellular respiration were
completely reversible within one hr. A dose-related decrease of DNP stimulated
oxygen consumption was observed when chloroform
was present. Succinate-stimulated oxygen consumption was not abolished by up to
10 mM chloroform.
... Chloroform
was administered to rats and mice by inhalation. High doses (300 ppm/6 hr/day
for 7 days) caused significant hepatotoxicity and mild renal toxicity. Both
hepatotoxicity and renal toxicity were observed in rats. The rats developed a
series of nasal lesions involving degeneration of Bowman's glands and osseous
hyperplasia.
The primary cellular target /of chloroform/
is the proximal tubule with no primary damage to the glomerulus or the distal
tubule. Proteinuria, glucosuria, and increased blood urea nitrogen levels are
all characteristic of chloroform-induced
nephrotoxicity.
... Castration of male mice decreased renal
cytochrome p450 and chloroform-induced
nephrotoxicity. Likewise, testosterone pretreatment of female mice increased
cytochrome p450 content and rendered female mice susceptible to the nephrotoxic
effects of chloroform.
... Chloroform
... /administered ip/ produced moderate increases in mouse striatal p-tyramine.
/Dose not specified/
National Toxicology Program Studies:
The effect of chloroform
on fertility & reproduction in Swiss CD-l mice was evaluated by use of a
Continuous Breeding protocol. Chloroform
was admin via gavage using corn oil as the vehicle. Based on a 14-day,
dose-finding study, 8, 20, & 50 mg/kg bw were chosen to test its effect on
fertility & reproduction. Based on the reference analyses of representative
aliquots of dosing soln, it was estimated that the actual doses received were
6.6, 16, & 41 mg/kg bw in the low, mid & high dose groups, respectively.
Both male & female mice (20 pairs/treatment group, 40 pairs for control
animals) were dosed daily for 7 days prior to & during a 98-day cohabitation
period. The F1 generation from the control & high dose groups was also
evaluated. At the high dose, chloroform
treatment had no apparent effect on fertility or reproduction in either parental
(F0) or F1 generation. F1 generation males in the high dose group showed
significantly increased epididymal weights & degeneration of epididymal
ductal epithelium. However, epididymal sperm motility, sperm count & sperm
morphology were not affected. F1 females in the high dose group showed increased
liver weight & there were signs of hepatocellular degeneration. It is
concluded that chloroform is not a
selective reproductive toxicant in Swiss CD-1 mice.
Non-Human Toxicity Values:
LD50 Rat intragastric 2000 mg/kg
LD50 White rat oral 2180 mg/kg
LD50 Rabbit oral 9827 mg/kg
LD50 Dog oral 2250 mg/kg
LD50 RAT MALE ORAL 908 MG/KG
LD50 RAT FEMALE ORAL 1117 MG/KG
LC50 Rat ihl 47,702 mg/cu m/4 hr
LD50 Mouse oral 36 mg/kg
LD50 Mouse ip 623 mg/kg
LD50 Mouse sc 704 mg/kg
LD50 Dog ip 1000 mg/kg
Ecotoxicity Values:
LC50 Salmo gairdneri (rainbow trout) 2030 ug/l
soft water, 1240 ug/l hard water (40% teratogenesis), 27 day flow-through tests
(20 min after fertilization to 8 days after hatching)
LC50 Penaeus duorarum (pink shrimp) 81,500 ug/l/96
hr static test
LC50 Salmo gairdneri (rainbow trout) 43,800 ug/l/96
hr static test
LC50 Lepomis macrochirus (bluegill) 100,000 ug/l/96
hr static test
LC50 Micropterus salmoides (largemouth bass)
51 ppm/96 hr /Conditions of bioassay not specified/
LC50 Ictalurus punctatus (channel catfish) 75
ppm/96 hr /Conditions of bioassay not specified/
LC50 Daphnia magna (cladoceran) 28,900 ug/l/48
hr in a static bioassay
LC50 Limanda sp (dab) 28 mg/l/96 hr
TSCA Test Submissions:
The toxicokinetics of chloroform
(CAS # 67-66-3, CHCl3) was systematically evaluated and interpreted in various
species including B6C3F1 mice, Fischer 344 and male Osborne-Mendel rats, and
male Syrian Golden hamsters for development and validation of a
physiologically-based pharmacokinetic (PB-PK) model of prospective dose-,
species- and route-specific disposition of CHCl3. This model assumes total chloroform
metabolism within target organs, liver and kidney, solely by a mixed function
oxidase (MFO) metabolic pathway following Michaelis-Menten kinetics. Metabolic
rate constants (Vmax, Km, and V/S), calculated by computer optimization of
multispecies enzyme activity and kinetics studies in liver and kidney, allowed
extrapolation of results between species. The model facilitates determination of
a "delivered dose" (macromolecular binding, MMB) of chloroform
metabolites to chloroform-sensitive
internal organs to imply a potential cytotoxicity and tumorigenicity associated
with chronic CHCl3 exposure. Toxicologically-significant descending relative
rates of chloroform sensitivity in
mice, rats, and humans were revealed. In chronic inhalation study with B6C3F1
mice, tumorigenicity correlated better with the rate of MMB (and a cellular
regenerative response) than with absolute metabolite or MMB levels. Inclusion of
historical absorption rates through digestive, respiratory, and circulatory
compartments in the mammalian model allowed toxicological simulations based on
route of administration. A homologous biochemical response provides a basis for
the extrapolation of toxicity associated with the relatively high chronic
exposures in studies with laboratory animals to that expected in humans
chronically exposed to lower levels of chloroform
typically encountered in the environment. Phase two studies will attempt to
correlate rates of cytotoxicity and cell death to MMB. The authors offered that
such a PB-PK model might be used for quantification of the potential biohazard
to humans chronically exposed to low level trichloromethane
found in chlorine-pretreated drinking water.
Chloroform
(CAS # 67-66-3) bioactivation and toxicity in the kidney and liver was
investigated in B6C3F1 mice and in male Osborne-Mendel rats exposed in an
environmental chamber to target vapor concentrations of 0, 10 (mice only), 100
(mice only), 400, and 1100 ppm for approximately 6 hours. Groups of 4 mice and 4
rats from each treatment level were sacrificed for quantification of nonprotein
sulfhydryl (NPSH, to approximate glutathione) levels in liver and kidney tissues
at 0, 2, 4, and 6 hours into the exposures and at 6, 12, 24, 46, and 48 hours
following final exposures. In mice, treatment was associated with significant
mortality 36 hours following 400 and 1100 ppm exposures, lethargy and perineal
staining (400, 1100 ppm), and light anesthesia (1100 ppm). Upon necropsy, livers
and kidneys appeared pale as compared to those of sham controls. In rats, light
anesthesia upon 1100 ppm exposures alone characterized the clinical toxicity and
no gross pathology was identified upon terminal necropsy. Renal NPSH levels were
statistically significantly (Winer's paired t-test) depressed for prolonged
periods following exposures of 100 ppm and above in mice, while NPSH levels
either equalled or slightly exceeded those of sham control animals in rats of
exposures below 1100 ppm. Conversely, mouse hepatic NPSH levels dropped markedly
at isolated sampling times only, the NPSH depressions inconsistent and not dose
related, but more profound in association with 400 and 1100 ppm than with 10 and
100 ppm exposures. In rats, both renal and liver NPSH levels were statistically
significantly (Winer's paired t-test) depressed at 4-hour sampling following
1100 ppm exposures. These studies contributed to derivation of metabolic and
bioactivation rate constants in design of a physiologically-based
pharmacokinetic (PB-PK) model of chloroform
toxicity.
The metabolic disposition of chloroform
(CAS # 67-66-3, CHCl3) was evaluated in male B6C3F1 mice (4/group) and
Osborne-Mendel rats (3/group) exposed under dynamic flow-through conditions in a
Roth-type metabolism chamber to target vapor concentrations of 10 (mice only),
100, 400 and 1100 (rats only) ppm 14CHCl3 for 6 hours. Urine, feces, and CO2
were collected and analyzed for radioactive label both during and after
exposure. Likewise, aqueous samples of carcass homogenates (33-50% w/w) and
skin, harvested during terminal sacrifice of all test animals 48 hours post
exposure, were analyzed to quantify fixed radiolabel. At exposures of 400 ppm,
metabolism of 14CHCl3 appeared to become saturating (non-linear) in both mice
and rats, with the radioactive body burden recovered as metabolites (mice 92%;
rats 80%) diminished relative to that at 100 ppm (98-99%). Additionally,
post-exposure metabolism and unmetabolized 14CHCl3 collected following exposures
in excess of 100 ppm increased disproportionately. Exhaled 14CO2, urine, and
feces, respectively, accounted for approximately 85%, 10%, and 1-1.5% of the
total radiolabeled CHCl3 metabolized; the carcass and skin accounted for
approximately 3% and 1%, respectively. On comparison, elimination routes and
rates were highly consistent in mice and rats, although the total body burden
(mg/kg) in mice was 2-4X that in rats. These studies contributed to derivation
of metabolic rate constants in design of a physiologically-based pharmacokinetic
(PB-PK) model of chloroform toxicity.
The metabolic disposition of chloroform
(CAS # 67-66-3, CHCl3) was evaluated in male B6C3F1 mice (4/group) and
Osborne-Mendel rats (3/group) exposed under dynamic flow-through conditions in a
Roth- type metabolism chamber to target vapor concentrations of 10 (mice only),
100, 400, and 1100 (rats only) ppm 14CHCl3 for 6 hours. All animals were
sacrificed at 6 hours post exposure for harvest and assay of liver and kidneys
to assess the degree of irreversible macromolecular binding (MMB), or the
"delivered dose" (Anderson, 1987) of radiolabel chloroform
or its metabolites. At low exposure levels (10, 100 ppm), mouse kidney MMB
(1.06, 4.01 nmol Eq/mg protein) was 4-10 fold greater than liver MMB (0.10, 1.05
nmol Eq/mg protein), while these values converged at 400 ppm (4.99 and 4.48 nmol
Eq/mg protein for liver and kidney, respectively). Conversely, at exposure
levels of 100 and 400 ppm, rat liver MMB (0.60, 1.33 nmol Eq/mg protein) and
kidney MMB (0.66, 0.89 nmol Eq/mg protein) were roughly equivalent, while these
values diverged between 400 and 1100 ppm, such that liver MMB after a 1100 ppm
exposure (1.70 nmol Eq/mg protein) was approximately 2X kidney MMB (0.78 nmol Eq/mg
protein). Mouse MMB was higher, on comparison, than that in the rat at the same
exposure levels, consistent with a higher rate of CHCl3 metabolism. These values
became an integral component of a physiologically-based pharmacokinetic (PB-PK)
model of chloroform toxicity.
The rate of chloroform
(CAS # 67-66-3, CHCl3) metabolism was evaluated in 6-hour in vitro bioassay with
microsomal fractions of liver and kidney from B6C3F1 mice, F344 rats, Syrian
Golden hamsters, and humans. Microsomal protein preparations of each species
were incubated for 30 minutes with labeled 14CHCl3 in dimethyl formamide, a
NADPH regenerating system and a potassium phosphate buffer (pH 7.4). Boiled
enzyme preparations containing equivalent amounts of protein served as controls.
The reaction terminated at 30 minutes, CO2 generated by the enzymatic reaction
was measured and the solution's unreacted substrate (14CHCl3) and water-soluble
reaction products separated by solvent extraction (unlabeled CHCl3). Liquid
scintillation assay in combined species analysis (mice, rats, hamsters, and
humans) documented a rate of 14CHCl3 biotransformation to water-soluble
metabolite proportional to time for 10-30 min and proportional to protein
concentration up to 1-2 mg protein per incubation. This reaction was wholly
inhibited by boiling the enzyme prior to incubation. Reaction rates or MFO
(mixed function oxidase) activities (nmoles oxidized/min/mg protein at
0.049-0.058 mM CHCl3) in liver microsomes of mouse, rat, and hamster ranged from
0.0199 (rat) to 0.133 (hamster) nmoles/min/mg protein. Human liver microsomes
demonstrated a broad activity range from 0.003 - 0.017 nmoles/min/mg protein
(mean +/- s.d. = 0.00816 +/- 0.00448), the slowest rates among tested mammals.
Descending rates of CHCl3 metabolism in the kidney were found in mice (0.0102
nmoles/min/mg protein), hamsters (0.00562 nmoles/min/mg protein), and rats
(0.000928 nmoles/min/mg protein). Human kidney samples were limited and failed
to demonstrate microsomal rates of CHCl3 metabolism above the minimal detection
limit (0.0003 nmoles/min/mg protein at 0.06 mM CHCl3). Species-specific
metabolic indices were subsequently derived by computer optimization of kinetics
study data associated with 1-20 mM 14CHCl3 for development of a
physiologically-based pharmacokinetic (PB-PK) model of chloroform
toxicity.
Chloroform
(CAS # 67-66-3) was evaluated for developmental toxicity in pregnant Wistar rats
(23-25/group) exposed by inhalation at concentrations of 0, 30, 100, and 300 ppm
for 7 hours/day during Days 7-16 postconception. Treatment was associated with
dose-related depression of maternal food consumption and bodyweight gains,
primarily during the first week of treatment; no further signs of maternal
toxicity and no gross pathology were observed. Signs of embryotoxicity included
dose-dependent early intrauterine loss of primordia with slightly stunted
development (slightly reduced crown-rump length) among the remaining live
fetuses at all treatment levels. No toxicologically significant incidence of
malformations was observed on Day 21 terminal necropsy of treated and control
fetuses relative to spontaneous occurrence in experimental controls.
Chloroform
(CAS # 67-66-3) was evaluated for clastogenicity in Chinese Hamsters
(5/sex/treatment group) exposed by oral gavage to doses of 0 (solvent control),
40, 120, and 400 mg/kg bw with subsequent harvest, preparation and analysis of
metaphase bone marrow cells (100 cells/animal) at 6 (high dose), 24 (all doses),
and 48 (high dose) hours post-treatment. Hamsters of 400 mg/kg doses exhibited
signs of toxicity including hypoactivity, closed eyes, and arrested food
consumption. Slight enhancement of chromosomal aberrations was statistically
significant (Mann-Whitney-U-test) 6 and 24 hours after doses of 400 mg/kg,
although the rate was still within the range of historical negative controls.
Further, outside the range of historical controls, no dose-response relationship
was demonstrated. The study authors noted an inference of chloroform
mutagenicity, however, based on the nature of marked damage (multiple
aberrations, chromosomal disintegration, and exchanges) associated with oral chloroform
at doses of 120 and 400 mg/kg (6-, 24-, and 48-hour assessments). In repeat
study, exposing groups of hamsters to doses of 0 (solvent control), 120, and 400
mg/kg bw, 24-hour cytogenetic assay again revealed a slight but statistically
significant increase in chromosome aberrations in association with 400 mg/kg
doses, failing again to demonstrate a dose-response relationship for rates of
damage (chromosome breaks) beyond the range of historical controls. Distinctly
heavy damage (multiple aberrations and exchanges) characterized the chloroform-induced
aberrations at 400 mg/kg in 6/6000 metaphase bone marrow cells.
Metabolism/Pharmacokinetics:
Metabolism/Metabolites:
WHEN (14)C-CHLOROFORM
WAS ADMIN ORALLY TO MICE, RATS, & MONKEYS, RADIOACTIVITY WAS FOUND IN
EXPIRED AIR. MOST OF DOSE WAS EXCRETED UNCHANGED BY MONKEYS, AS (14)CO2 (CARBON
DIOXIDE) BY MICE, & AS BOTH BY RATS. THREE METABOLITES WERE DETECTED IN
URINE OF RATS & MICE, ONE OF WHICH WAS IDENTIFIED AS UREA.
HALOFORMS ARE METABOLIZED TO CARBON MONOXIDE
BY HEPATIC MICROSOMAL MIXED FUNCTION OXIDASES & THIS REACTION IS MARKEDLY
STIMULATED BY SULFHYDRYL CMPD. MAX STIMULATION OCCURRED AT 0.5 MMOL GLUTATHIONE.
A MECHANISM FOR CONVERSION TO CARBON MONOXIDE IS PROPOSED.
TRIHALOMETHANES (HALOFORMS) WERE METAB TO
CARBON MONOXIDE BY RAT LIVER MICROSOMAL FRACTION REQUIRING NADPH & MOLECULAR
OXYGEN. METABOLISM FOLLOWED HALIDE ORDER; THUS, CHLOROFORM
YIELDED SMALLEST AMT. RESULTS SUGGEST CYTOCHROME P450 DEPENDENT SYSTEM.
Deuterium-labeled chloroform
was less toxic and less readily metabolized than /normal/ chloroform,
suggesting that the cleavage of the C-H bond is the rate-limiting step in the
process resulting in hepatotoxicity.
Whether chloroform-induced
nephrotoxicity might be due to its metabolism to phosgene in the kidney was
studied. Kidney homogenates from mice in the presence of glutathione metabolize chloroform
to 2-oxothiazolidine-4-carboxylic acid (OTZ) This product appears to be formed
by the initial trapping of COCl2 by 2 molecules of glutathione to form
diglutathionyl dithiocarbonate. Kidney gamma-glutamyl transpeptidase can rapidly
metabolize diglutathionyl dithiocarbonate to
N-(2-oxothiazolidine-4-carbonyl)glycine which is then hydrolyzed, possibly by
cysteinyl glycinase to 2-oxothiazolidine-4-carboxylic acid. The finding that
deuterium-labeled chloroform was less
nephrotoxic and depleted less renal glutathione than did chloroform
suggests that the metabolism of chloroform
to phosgene also occur in the kidney in vivo and lead to nephrotoxicity.
While the liver is the primary site for chloroform
metabolism, other tissues, including the kidney, can also metabolize chloroform
to carbon dioxide.
... Relation between metabolism and toxicity
of chloroform in the kidney of
rabbits, a species in which renal cytochrome p450 is induced by phenobarbital.
Pretreatment with phenobarbital enhanced the toxic response of renal cortical
slices to chloroform in vitro as
indicated by decreased p-aminohippurate and tetraethylammonium (+1)
accumulation. Phenobarbital pretreatment also potentiated in vitro (14)C-chloroform
metabolism to (14)carbon dioxide and covalently bound radioactivity in rabbit
renal cortical slices and microsomes. Addition of L-cysteine significantly
reduced covalent binding in renal microsomes from phenobarbital-treated and
control rabbits and was associated with the formation of
2-oxothiazolidine-4-carboxylic acid. Formation of 2-oxothiazolidine-4-carboxylic
acid was enhanced in renal microsomes from phenobarbital-treated rabbits. Thus,
the kidney metabolizes chloroform to
phosgene.
Studies were made with male Wistar rats on the
effects of 50% food restriction on the metabolism of ... chloroform.
... The activities of liver drug-metabolizing enzymes for this solvent was
enhanced almost equally without exception by one-day food restriction, although
the restriction produced no significant increase in the microsomal protein and
cytochrome p450 contents. Thus, food restriction enhances metabolism of chloroform
in the liver.
Rats were injected iv or ip with (14)C chloroform
and the localization and binding of metabolites in the tissues were studied by
whole-body and microautoradiography. Based on the the autoradiographic findings
various tissues were tested for their capacity to form (14)CO2 and to
incorporate (14)C into tissue-macromolecules from the (14)C chloroform.
Autoradiography in vitro was used to localize the sites of (14)C chloroform
metabolism under in vitro conditions. The results of the in vitro metabolism
studies showed that several tissues had a capacity to metabolize the (14)C chloroform.
Further, the results showed that there was a correlation between the ability of
various tissues to accumulate metabolites in the rats injected with the (14)C chloroform
and the ability of the same tissues to metabolize the (14)C chloroform
in vitro. The in vitro autoradiography showed an accumulation of radioactivity
at sites corresponding to the ones accumulating metabolites in vivo. It is
concluded that many tissues have a capacity to metabolize chloroform
in vivo and in vitro. The structures identified to have a marked chloroform-metabolizing
capacity were, besides the liver, the kidney cortex, the mucosa of the bronchial
tree, the tracheal mucosa, the olfactory and respiratory nasal mucosa. Bowman's
glands in the olfactory lamina propria mucosae, Steno's gland (the lateral nasal
gland), the mucosa of the oesophagus, the larynx, the tongue, the gingiva, the
cheek, the nasoparyngeal duct, the pharynx and the soft palate (but not the hard
palate).
Hepatic lipoperoxidation by highly reactive
metabolites produced during biodegradation of chloroform
is believed to cause delayed hepatic necrosis. Chemilluminescence occurs during
interaction of these metabolites with a lipid membrane. We have made continuous
in vivo measurements of hepatic light output in the phenobarbital-induced rat
breathing either air or chloroform
vaporized in air. The data permitted direct estimation of the time course of chloroform-induced
lipoperidoxidation. These potentially toxic events began 15 minutes after
initiation of anesthesia and continued for the duration of the study.
Chemiluminescence did not occur with inhalation of isoflurane, an anesthetic
undergoing minimal biodegradation.
IN VITRO ... FINDING OF
2-OXO-THIAZOLIDINE-4-CARBOXYLIC ACID IN INCUBATES WAS STRONG EVIDENCE FOR
FORMATION OF PHOSGENE; REACTIVE METABOLITE, PHOSGENE IS FORMED BY MIXED-FUNCTION
OXIDATION OF CHLOROFORM TO
TRICHLOROMETHANOL ... /WHICH UNDERGOES/ DEHYDROCHLORINATION.
Absorption, Distribution & Excretion:
CHLOROFORM
CAN BE ABSORBED THROUGH LUNG, FROM GI TRACT & TO SOME EXTENT THROUGH SKIN.
INHALATION ROUTE IS ... PRIMARY SOURCE OF ... ABSORPTION IN MAN.
CHLOROFORM
IS RAPIDLY ABSORBED & DISTRIBUTED TO ALL ORGANS, WITH RELATIVELY HIGH CONCN
IN NERVOUS TISSUE. AFTER INTRADUODENAL INJECTION OF (14)C-CHLOROFORM
TO RATS, 70% ... WAS FOUND UNCHANGED IN EXPIRED AIR & 4% AS (14)CO2 (CARBON
DIOXIDE) DURING 24 HR. ... LIVER &, TO MUCH LESSER EXTENT, KIDNEY WERE MAIN
ORGANS IN WHICH CO2 WAS FORMED.
IN MAN, PULMONARY EXCRETIONS OF CHLOROFORM
& ITS CO2 (CARBON DIOXIDE) METAB ACCOUNT SUBSTANTIALLY FOR SINGLE ORAL DOSE
OF 0.5 OR 1.0 G. AMONGST 9 SUBJECTS, UP TO 68% OF DOSE IS EXCRETED UNCHANGED
& UP TO 51% OF CO2; NOT MORE THAN 4% OF DOSE IS EXCRETED UNCHANGED AFTER 8
HR.
... /CHLOROFORM
CROSSES/ PLACENTA RAPIDLY & ENTERS FETAL CIRCULATION.
Long-term retention of chloroform
occurred in body fat, with incr levels occurring in liver during the
post-exposure period. Thus, there is redistribution of chloroform
in body tissues as it slowly builds up in fatty tissues during the post exposure
period.
Chloroform
is well absorbed via the respiratory system (94% to 77%). ... Absorption from
the gastrointestinal tract approximates 100%.
Distribution of radioactivity in pregnant mice
was registered at different time intervals (0-24 hr) after a 10 min period of
inhalation of (14)C-labeled chloroform
and methyl chloroform.
Autoradiographic and liquid scintillation methods were used to make possible the
distinction between volatile (non-metabolized), water-soluble and firmly
tissue-bound radioactivity. Methyl chloroform
was retained longer in fat as compared to chloroform.
Metabolites of chloroform were present
in a much greater abundancy than those of methyl chloroform
and they were found preferentially in the respiratory tract (nasal mucosa,
trachea and bronchi), liver and excretory organs. Tissue-bound activity after Chloroform
inhalation or ip injection to newborn mice was found in the respiratory tract
and centrilobular areas of the liver. Volatile radioactivity was observed in the
placenta and fetuses at short time intervals after inhalation of both chloroform
and methyl chloroform at all stages of
gestation. ... Metabolites accumulated in the embryonic neural tissues.
Tissue-bound metabolites of chloroform
were observed in the fetal respiratory epithelium.
By using the (14)C-labeled compounds, the
absorption, distribution, and excretion of trichloromethane
... was determined in rats (100 mg/kg) or in mice (150 mg/kg) after intragastric
intubation; most or all the compound was eliminated in both rats and mice by the
lung in the expired air. In rats, 40-81% of the compound was expired as
(14)C-carbon dioxide and approximately 5-26% as unmetabolized parent. In mice,
4-18% was expired as (14)C-carbon dioxide and approximately 41-67% as parent.
In 6 acute fatalities due to the intentional
or forced inhalation of chloroform,
blood levels of 10-48 mg/l and urine levels of 0-60 mg/l were observed.
Mechanism of Action:
Mechanisms of chloroform
and carbon tetrachloride toxicity to primary cultured male B6C3F1 mouse
hepatocytes were investigated. The cytotoxicity of both chloroform
and carbon tetrachloride was dose and duration dependent. Maximal hepatocyte
toxicity, as determined by lactate dehydrogenase leakage into the culture
medium, occurred with the highest concentrations of chloroform
(5 mM) and carbon tetrachloride (2.5 mM) used and with the longest duration of
treatment (20 hr). Carbon tetrachloride was approximately 16 times more toxic
than chloroform to the hepatocytes.
The toxicity of these compounds was decreased by adding the mixed function
oxidase system inhibitor, SKF-525A (25 microM) to the cultures. The addition of
diethyl maleate (0.25 mM), which depletes intracellular glutathione (GSH)-potentiated
chloroform and carbon tetrachloride
toxicity. The toxicity of chloroform
carbon tetrachloride could also be decreased by adding the antioxidants
N,N'-diphenyl-p-phenylenediamine (25 microM), alpha-tocopherol acetate (Vitamin
E) (0.1 mM), or superoxide dismutase (100 U/ml) to the cultures. These results
suggest that: in mouse hepatocytes, both chloroform
and carbon tetrachloride are metabolized to toxic components by the mixed
function oxidase system; GSH plays a role in detoxifying those metabolites; free
radicals are produced during the metabolism of chloroform
and carbon tetrachloride and free radicals may be important mediators of the
toxicity of these two halomethanes.
The feasibility of an oxygen-independent
mechanism of chloroform bioactivation
was indicated by the covalent binding to lipid and protein occurring in
anaerobic incubations of chloroform
and microsomes in the presence of NADPH. Under these conditions, the loss of
cytochrome p450 and the inhibition of related mono-oxygenases were also
observed. The chloroform anoxic
biotransformation was negligible in uninduced microsomes and seemed to be
catalyzed mainly by phenobarbital-inducible p450 isozymes. Biotransformation
could also be supported by NADH as the source of reducing equivalents. Anaerobic
metabolism of chloroform led to
decreased levels of the main phenobarbital-induced p450 isozymes even at low chloroform
concentration, and did not affect benzo(a)pyrene hydroxylase activity. These
effects were not decreased by thiolic compounds. The oxidation products of chloroform
caused a general impairment of the monoxygenase system, probably related to the
formation of protein aggregates with very high molecular weight. In the presence
of physiological concentrations of GSH, the targets of aerobically-produced
metabolite were lipids, and, to a smaller extent, p450. At low chloroform
concentrations and/or in the presence of GSH, the most changes to microsomal
structures seemed to be produced by the reductively-formed intermediates.
Interactions:
ONE SERIOUS DRUG INTERACTION INVOLVES
SENSITIZATION OF MYOCARDIUM TO CATECHOLAMINES BY ... HALOGENATED HYDROCARBON
ANESTHETICS (EG, CHLOROFORM ...) IN
PRESENCE OF THESE ANESTHETICS, ADMIN OF EPINEPHRINE, ISOPROTERENOL, OR
LEVARTERENOL MARKEDLY INCR INCIDENCE OF CARDIAC ARRHYTHMIAS.
EFFECTS /OF CHLOROFORM/
ON LIVER & KIDNEYS ARE EXAGGERATED BY ... INGESTION OF ALCOHOLIC BEVERAGES.
... DDT & PHENOBARBITONE POTENTIATED CHLOROFORM-INDUCED
LIVER DAMAGE IN RATS ...
ADMIN OF KEPONE (CHLORDECONE) RESULTED IN
MARKED POTENTIATION OF CHLOROFORM
INDUCED HEPATOTOXICITY WHEREAS PRETREATMENT WITH MIREX HAD NO EFFECT ON LIVER
INJURY.
Cysteine treatment reduced both covalent
binding and hepatotoxicity, while diethyl maleate treatments incr both the
hepatotoxicity of chloroform and the
covalent binding of chloroform
metabolites to hepatic proteins.
Chloroform
(CHCl3)-induced liver injury was evaluated in male Sprague-Dawley rats
pretreated (15 mmol/kg, po) acetone (Ac), 2-butanone (Bu), 2-pentanone (Pn),
2-hexanone (Hx) or 2-heptanone (Hp). After 18 hr, a challenging dose of chloroform
(0.50 or 0.75 ml/kg, ip) was given. Liver damage was evaluated 24 hr after chloroform
admin by determining elevations in plasma GPT and OCT activity. Neither acetone,
2-butanone, 2-pentanone, 2-hexanone, 2-heptanone or the challenging dosages
produced marked liver injury when given alone. However, each of the ketones
potentiated chloroform-induced liver
damage. The severity of the potentiated hepatotoxic response was significantly
(positively) correlated with the ketone carbon chain length.
Oral admin of diethyldithiocarbamic acid and
carbon disulfide protected mice against chloroform-induced
kidney injury, as evidenced by normalization of delayed plasma
phenolsulfonophthalein clearance, suppression of incr kidney Ca content, and
prevention of renal tubular necrosis.
Rats were treated with (14)C-chloroform
(CHCl3) in corn oil or corn oil alone (CO) 8 hr following pretreatment with
2-hexanone in corn oil or corn oil alone. Livers were removed, homogenized 1, 2,
and 6 hr post-(14)CHCl3 administration, and glutathione content, irreversible
binding of (14)CHCl3-derived radiolabel, and phospholipid composition were
determined. The combination of 2-hexanone + CHCl3 reduced glutathione content to
21% of control (CO + CO) /SRP: pretreatment and sham control/ 1 hr after CHCl3
administration. No significant rebound of glutathione was observed 24 hr
post-CHCl3 administration. In contrast, glutathione was not altered by
administration of CHCl3 to CO-pretreated rats. Although (14)CHCl3-derived
radiolabel was irreversibly bound to hepatic macromolecules of both CO- and
2-hexanone pretreated rats, total irreversibly bound (14)C was significantly
enhanced in 2-hexanone pretreated rats at all time points. The latter
observation was consistent with the decrease in glutathione of 2-hexanone
pretreated rats. Total (14)C binding in 2-hexanone pretreated rats reached a
plateau 2 hr post-(14)CHCl3 administration and was distributed 52% in protein,
41% in lipid, and 7% in acid soluble fractions 6 hr post-(14)CHCl3
administration. 2-Hexanone enhanced (14)C binding to protein and lipid at each
time point. Radiolabel was not detected in neutral lipids of control or
2-hexanone treated animals, but was enhanced 33-fold in phospholipids of
2-hexanone treated animals. Phospholipid fatty acid methyl ester derivatives did
not contain (14)C indicating the radiolabel was most likely associated with
phospholipid polar head groups. Two dimensional thin layer chromatographic
analysis of phospholipid from treated animals demonstrated that 87% of the total
radiolabel was associated with a specific phospholipid which had a 1:1 molar
ratio of phosphate to (14)C.
... When given together, ... /chloroform
and carbon tetrachloride/ increased the toxic response in rats. ...
Histopathological changes were more severe from the combination than from either
chemical alone. Although the mechanism of the hepatotoxic interaction between chloroform
and carbon tetrachloride is unclear, ... there might be a combined effect of
phosgene formation and lipid peroxidation initiation.
Exposure to chlordecone (CD, Kepone) is known
to increase the hepatotoxicity of chloroform
in rats. A time-course analysis was conducted relating several indices of
biotransformation capacity with the ability of chlordecone to potentiate chloroform-induced
hepatotoxicity. Male Sprague-Dawley rats were given a single administration of
corn oil alone or chlordecone (50 mg/kg, po) dissolved in corn oil. At 2, 4, 8,
16, 20, 24, or 32 days posttreatment, groups of rats were killed and their
livers were analyzed for (i) cytochrome p450, NADPH-dependent cytochrome c
reductase, cytochrome b5 and glutathione content or (ii) in vitro irreversible
binding of (14)CHCl3-derived radiolabel to microsomal protein. Similarly treated
rats were challenged (2-32 days posttreatment) with chloroform
(0.5 ml/kg po); 24 hr later, liver damage was assessed by plasma alanine
aminotransferase, plasma ornithine carbamyl transferase, plasma bilirubin, and
hepatic glucose-6-phosphatase. Chlordecone potentiation was maximal &
persisted up to 20-24 days post-chlordecone treatment.
Characteristics of chloroform
nephrotoxicity and of 2-hexanone potentiation were evaluated in adult male
Fischer 344 rats pretreated with vehicle (oil, 10 ml/kg, po) or 2-hexanone (10
mmol/kg, po) 18 hr prior to chloroform
exposure. Little metabolism of (14)chloroform
by renal cortical microsomes from vehicle- or 2-hexanone-pretreated rats was
detected. However, chloroform produced
a concn-related dysfunction when added to renal cortical slices from Fischer 344
or Sprague-Dawley rats. The degree of chloroform
toxicity in vitro was not altered when renal cortical slices were preincubated
with chloroform (8.5 microliter) under
an atmosphere of carbon monoxide. In renal cortical slices, deuterated-chloroform
was less toxic than chloroform.
Although 2-hexanone pretreatment increased renal slice metabolism of (14)chloroform
twofold, this incr was not associated with an incr in nephrotoxicity after
direct exposure of slices to chloroform
(0 to 10 microliter) in vitro. Chloroform
(0.5 ml/kg, ip) did not alter renal cortical glutathione concn in vehicle or
2-hexanone pretreated rats. The association of (14)chloroform-derived
radiolabel was incr over control by 2-hexanone pretreatment in protein, lipid,
and acid soluble fractions from the renal cortex by approx two-, two-, and
five-fold, respectively. In conclusion, renal cytochrome p450 did not appear to
mediate chloroform metabolism and
nephrotoxicity in the rat to the extent observed previously in mice. 2-Hexanone
appeared to potentiate nephrotoxicity by a mechanism different than that
observed in rat liver.
Administration of chloroform
to male C57/6J (C57) and DBA/2J (DBA) mice produced dose-dependent hepatic and
renal damage. Hepatic aryl hydrocarbon hydroxylase activity was higher in C57
than in DBA mice; in kidney, aryl hydrocarbon hydroxylase activity was higher in
DBA than in C57 mice. Chloroform
caused the same degree of liver damage in both strains of mice; however,
nephrotoxicity of chloroform was
greater in DBA than in C57 mice. Pretreatment of C57 and DBA mice with
phenobarbital markedly increased hepatic aryl hydrocarbon hydroxylase activity
and hepatotoxicity of chloroform in
both strains but did not affect renal aryl hydrocarbon hydroxylase or
nephrotoxicity of chloroform.
Similarly, beta-naphthoflavone (BNF) enhanced chloroform
hepatotoxicity in C57 mice, but has little effect on nephrotoxicity. BNF did not
affect chloroform-induced hepatic
injury in male DBA mice. Pretreatment with polybrominated biphenyl enhanced aryl
hydrocarbon hydroxylase activity in liver and chloroform
hepatotoxicity in both strains. After polybrominated biphenyl, nephrotoxicity of
chloroform and renal aryl hydrocarbon
hydroxylase activity were increased in C57 mice, whereas polybrominated biphenyl
did not alter nephrotoxicity or renal aryl hydrocarbon hydroxylase in DBA mice.
Thus, chloroform nephrotoxicity is
independent of hepatotoxicity.
... Ethanol ... increased the toxicity of chloroform
...
Pharmacology:
Therapeutic Uses:
MEDICATION (VET): AS INHALATION ANESTHETIC IN
HORSES & NOW RARELY IN CATTLE, SHEEP, CATS OR DOGS BECAUSE OF DANGEROUS
COMPLICATIONS & SUPERIOR ALTERNATIVES; INTERNALLY, WELL DIL IN INTESTINAL
COLIC & FLATULENCE; IN EXPECTORANTS, & LESS COMMONLY AS ANTHELMINTIC
(SWINE, DOGS) ... . /FORMER USE/
MEDICATION (VET): USED/ EXTERNALLY, AS
LINIMENT-TYPE COUNTERIRRITANT FOR RELIEF OF DEEP SEATED PAIN, TO EXPEL SCREWWORM
LARVAE FROM WOUNDS, AS SKIN CLEANSER (FAT SOLVENT), & AS SKIN COOLANT &
LOCAL ANESTHETIC DUE TO ITS EVAPORATION. ... INTERNALLY, IT IS GIVEN IN VARIOUS
MIXT WELL DIL TO AVOID GASTRIC IRRITATION ... . /FORMER USE/
HAS BEEN USED AS AN ANESTHETIC & IN
PHARMACEUTICAL PREPARATIONS.
Chloroform
was used chiefly as an anesthetic and in pharmaceutical preparation immediately
prior to World War II. However, these uses have been banned.
Drug Warnings:
Maternal Medication usually Compatible with
Breast-Feeding: Chloroform: Reported
Sign or Symptom in Infant or Effect on Lactation: None. /from Table 6/
Interactions:
ONE SERIOUS DRUG INTERACTION INVOLVES
SENSITIZATION OF MYOCARDIUM TO CATECHOLAMINES BY ... HALOGENATED HYDROCARBON
ANESTHETICS (EG, CHLOROFORM ...) IN
PRESENCE OF THESE ANESTHETICS, ADMIN OF EPINEPHRINE, ISOPROTERENOL, OR
LEVARTERENOL MARKEDLY INCR INCIDENCE OF CARDIAC ARRHYTHMIAS.
EFFECTS /OF CHLOROFORM/
ON LIVER & KIDNEYS ARE EXAGGERATED BY ... INGESTION OF ALCOHOLIC BEVERAGES.
... DDT & PHENOBARBITONE POTENTIATED CHLOROFORM-INDUCED
LIVER DAMAGE IN RATS ...
ADMIN OF KEPONE (CHLORDECONE) RESULTED IN
MARKED POTENTIATION OF CHLOROFORM
INDUCED HEPATOTOXICITY WHEREAS PRETREATMENT WITH MIREX HAD NO EFFECT ON LIVER
INJURY.
Cysteine treatment reduced both covalent
binding and hepatotoxicity, while diethyl maleate treatments incr both the
hepatotoxicity of chloroform and the
covalent binding of chloroform
metabolites to hepatic proteins.
Chloroform
(CHCl3)-induced liver injury was evaluated in male Sprague-Dawley rats
pretreated (15 mmol/kg, po) acetone (Ac), 2-butanone (Bu), 2-pentanone (Pn),
2-hexanone (Hx) or 2-heptanone (Hp). After 18 hr, a challenging dose of chloroform
(0.50 or 0.75 ml/kg, ip) was given. Liver damage was evaluated 24 hr after chloroform
admin by determining elevations in plasma GPT and OCT activity. Neither acetone,
2-butanone, 2-pentanone, 2-hexanone, 2-heptanone or the challenging dosages
produced marked liver injury when given alone. However, each of the ketones
potentiated chloroform-induced liver
damage. The severity of the potentiated hepatotoxic response was significantly
(positively) correlated with the ketone carbon chain length.
Oral admin of diethyldithiocarbamic acid and
carbon disulfide protected mice against chloroform-induced
kidney injury, as evidenced by normalization of delayed plasma
phenolsulfonophthalein clearance, suppression of incr kidney Ca content, and
prevention of renal tubular necrosis.
Rats were treated with (14)C-chloroform
(CHCl3) in corn oil or corn oil alone (CO) 8 hr following pretreatment with
2-hexanone in corn oil or corn oil alone. Livers were removed, homogenized 1, 2,
and 6 hr post-(14)CHCl3 administration, and glutathione content, irreversible
binding of (14)CHCl3-derived radiolabel, and phospholipid composition were
determined. The combination of 2-hexanone + CHCl3 reduced glutathione content to
21% of control (CO + CO) /SRP: pretreatment and sham control/ 1 hr after CHCl3
administration. No significant rebound of glutathione was observed 24 hr
post-CHCl3 administration. In contrast, glutathione was not altered by
administration of CHCl3 to CO-pretreated rats. Although (14)CHCl3-derived
radiolabel was irreversibly bound to hepatic macromolecules of both CO- and
2-hexanone pretreated rats, total irreversibly bound (14)C was significantly
enhanced in 2-hexanone pretreated rats at all time points. The latter
observation was consistent with the decrease in glutathione of 2-hexanone
pretreated rats. Total (14)C binding in 2-hexanone pretreated rats reached a
plateau 2 hr post-(14)CHCl3 administration and was distributed 52% in protein,
41% in lipid, and 7% in acid soluble fractions 6 hr post-(14)CHCl3
administration. 2-Hexanone enhanced (14)C binding to protein and lipid at each
time point. Radiolabel was not detected in neutral lipids of control or
2-hexanone treated animals, but was enhanced 33-fold in phospholipids of
2-hexanone treated animals. Phospholipid fatty acid methyl ester derivatives did
not contain (14)C indicating the radiolabel was most likely associated with
phospholipid polar head groups. Two dimensional thin layer chromatographic
analysis of phospholipid from treated animals demonstrated that 87% of the total
radiolabel was associated with a specific phospholipid which had a 1:1 molar
ratio of phosphate to (14)C.
... When given together, ... /chloroform
and carbon tetrachloride/ increased the toxic response in rats. ...
Histopathological changes were more severe from the combination than from either
chemical alone. Although the mechanism of the hepatotoxic interaction between chloroform
and carbon tetrachloride is unclear, ... there might be a combined effect of
phosgene formation and lipid peroxidation initiation.
Exposure to chlordecone (CD, Kepone) is known
to increase the hepatotoxicity of chloroform
in rats. A time-course analysis was conducted relating several indices of
biotransformation capacity with the ability of chlordecone to potentiate chloroform-induced
hepatotoxicity. Male Sprague-Dawley rats were given a single administration of
corn oil alone or chlordecone (50 mg/kg, po) dissolved in corn oil. At 2, 4, 8,
16, 20, 24, or 32 days posttreatment, groups of rats were killed and their
livers were analyzed for (i) cytochrome p450, NADPH-dependent cytochrome c
reductase, cytochrome b5 and glutathione content or (ii) in vitro irreversible
binding of (14)CHCl3-derived radiolabel to microsomal protein. Similarly treated
rats were challenged (2-32 days posttreatment) with chloroform
(0.5 ml/kg po); 24 hr later, liver damage was assessed by plasma alanine
aminotransferase, plasma ornithine carbamyl transferase, plasma bilirubin, and
hepatic glucose-6-phosphatase. Chlordecone potentiation was maximal &
persisted up to 20-24 days post-chlordecone treatment.
Characteristics of chloroform
nephrotoxicity and of 2-hexanone potentiation were evaluated in adult male
Fischer 344 rats pretreated with vehicle (oil, 10 ml/kg, po) or 2-hexanone (10
mmol/kg, po) 18 hr prior to chloroform
exposure. Little metabolism of (14)chloroform
by renal cortical microsomes from vehicle- or 2-hexanone-pretreated rats was
detected. However, chloroform produced
a concn-related dysfunction when added to renal cortical slices from Fischer 344
or Sprague-Dawley rats. The degree of chloroform
toxicity in vitro was not altered when renal cortical slices were preincubated
with chloroform (8.5 microliter) under
an atmosphere of carbon monoxide. In renal cortical slices, deuterated-chloroform
was less toxic than chloroform.
Although 2-hexanone pretreatment increased renal slice metabolism of (14)chloroform
twofold, this incr was not associated with an incr in nephrotoxicity after
direct exposure of slices to chloroform
(0 to 10 microliter) in vitro. Chloroform
(0.5 ml/kg, ip) did not alter renal cortical glutathione concn in vehicle or
2-hexanone pretreated rats. The association of (14)chloroform-derived
radiolabel was incr over control by 2-hexanone pretreatment in protein, lipid,
and acid soluble fractions from the renal cortex by approx two-, two-, and
five-fold, respectively. In conclusion, renal cytochrome p450 did not appear to
mediate chloroform metabolism and
nephrotoxicity in the rat to the extent observed previously in mice. 2-Hexanone
appeared to potentiate nephrotoxicity by a mechanism different than that
observed in rat liver.
Administration of chloroform
to male C57/6J (C57) and DBA/2J (DBA) mice produced dose-dependent hepatic and
renal damage. Hepatic aryl hydrocarbon hydroxylase activity was higher in C57
than in DBA mice; in kidney, aryl hydrocarbon hydroxylase activity was higher in
DBA than in C57 mice. Chloroform
caused the same degree of liver damage in both strains of mice; however,
nephrotoxicity of chloroform was
greater in DBA than in C57 mice. Pretreatment of C57 and DBA mice with
phenobarbital markedly increased hepatic aryl hydrocarbon hydroxylase activity
and hepatotoxicity of chloroform in
both strains but did not affect renal aryl hydrocarbon hydroxylase or
nephrotoxicity of chloroform.
Similarly, beta-naphthoflavone (BNF) enhanced chloroform
hepatotoxicity in C57 mice, but has little effect on nephrotoxicity. BNF did not
affect chloroform-induced hepatic
injury in male DBA mice. Pretreatment with polybrominated biphenyl enhanced aryl
hydrocarbon hydroxylase activity in liver and chloroform
hepatotoxicity in both strains. After polybrominated biphenyl, nephrotoxicity of
chloroform and renal aryl hydrocarbon
hydroxylase activity were increased in C57 mice, whereas polybrominated biphenyl
did not alter nephrotoxicity or renal aryl hydrocarbon hydroxylase in DBA mice.
Thus, chloroform nephrotoxicity is
independent of hepatotoxicity.
... Ethanol ... increased the toxicity of chloroform
...
Environmental Fate & Exposure:
Environmental Fate/Exposure Summary:
Chloroform's
production and use in the production of hydrochlorofluorocarbon 22 (HCFC-22) may
result in its release to the environment through various waste streams. Chloroform
has been shown to occur naturally in the environment as a plant volatile and in
peat bogs. If released to air, a vapor pressure of 197 mm Hg at 25 deg C
indicates chloroform will exist solely
as a vapor in the ambient atmosphere. Vapor-phase chloroform
will be degraded in the atmosphere by reaction with photochemically-produced
hydroxyl radicals; the half-life for this reaction in air is estimated to be 151
days. If released to soil, chloroform
is expected to have moderate mobility based upon a Koc value ranging from
153-196. Volatilization from moist soil surfaces is expected to be an important
fate process based upon a Henry's Law constant of 3.67X10-3 atm-cu m/mole. Chloroform
may volatilize from dry soil surfaces based upon its vapor pressure. Under
normal environmental conditions, chloroform
is not expected to undergo biodegradation in soil. However, several studies have
demonstrated that at low concns, chloroform
can be anaerobically degraded by methanogenic bacteria in the presence of a
primary substrate such as acetic acid. If released into water, chloroform
is not expected to adsorb to sediment and suspended solids in water based upon
its Koc values. Biodegradation of chloroform
in environmental aqueous environments is not well understood. Various reports
have both supported and refuted anaerobic biodegradation in water.
Volatilization from water surfaces is expected to be an important fate process
based upon this compound's Henry's Law constant. Estimated volatilization
half-lives for a model river and model lake are 1.3 hrs and 4.4 days,
respectively. BCF values ranging from 2.9-10.35 suggests bioconcentration in
aquatic organisms is low. Since chloroform
has a hydrolysis half-life of 1850 yrs at 25 deg C and pH 7, hydrolysis will not
be an environmentally important loss process. Occupational exposure to chloroform
may occur through inhalation and dermal contact with this compound at workplaces
where chloroform is produced or used.
The general population may be exposed to chloroform
via inhalation of ambient air, ingestion of food and drinking water. Chloroform
is widely detected in drinking water where the drinking water is chlorinated. (SRC)
Probable Routes of Human Exposure:
Shell Chem Co, Rocky Mountain Arsenal - mean
TWA were 2.6, 0.4 and 0.2 ppm for production operaters, drummers/bottle fillers
and maintenance/utility personnel (pesticide plant)(1). Polish pharmaceutical
plant 2 - 205 ppm(1); police forensic lab - 8 hr TWA - 15.8 ppm (range 2.6-46.4
ppm)(1); film manufacturing plant using a solvent containing 22% chloroform
1968-72 - 7-170 ppm (mean 47 ppm, 79 samples)(1).
NIOSH (NOES Survey 1981-1983) has
statistically estimated that 95,773 workers (41,397 of these are female) are
potentially exposed to chloroform in
the US(1). Occupational exposure to chloroform
may occur through inhalation and dermal contact with this compound at workplaces
where chloroform is produced or
used(SRC). The general population may be exposed to chloroform
via inhalation of ambient air(2,3), ingestion of food(2) and drinking
water(2,4).
Personal air concns of chloroform
were studied for 12 hr exposure periods(1). Forty eight people in New Jersey
during Feb 1983 had a mean personal exposure of 4.0 ug/cu m during day and
nighttime while 40 individuals in Los Angeles, CA during June 1987 had a mean
personal exposure of 3.8 ug/cu m during the day and 0.92 ug/cu m during
nighttime(1). In Antioch-Pittsburg, CA during June 1984, 68 people had a mean
personal exposure to chloroform of
0.47 ug/cu m during the day and 0.80 during nighttime(1). Several studies of
indoor swimming pools indicate that inhalation can provide substantial amounts
of chloroform(1). A study of 3 indoor
swimming pools and 3 life guards resulted in increases of personal air exposures
to chloroform(1). Personal air
exposures for the 3 lifeguards at the indoor pool were 95, 68, and 46 ug/cu m
while at home exposures dropped to 2.2, 2.0 and 5.2 ug/cu m(1). However, outdoor
pools showed no difference in personal air exposure to chloroform(1).
A pilot study carried out in Japan measured the intake of chloroform
from air, food, and tap water for 7 Japanese housewives on 3 consecutive days in
each of two seasons. For all 7 subjects in winter and 6 out of the 7 in summer,
food contributed the most to their daily intake, accounting for about half of
the daily intake of 37 ug in the summer and 70% of the smaller winter intake of
14 ug(1).
Several experiments indicate that dermal
absorption of chloroform during a
shower is roughly equivalent to inhalation exposure during the shower(1). It has
been estimated that about half the exposure from a 10-min shower is due to
dermal absorption(1). The major source of exposure to chloroform
is chlorination of water supplies(1). The results in exposure through ingestion
of drinking water, but also through inhalation and skin absorption as a result
of the myriad other uses of chlorinated water in the home: showers, baths,
washing clothes and dishes, etc supports this(1). At a typical personal exposure
to chloroform of about 3 ug/cu m(not
including exposure during the shower), this results in an estimated intake of
about 24 ug/day for women and 30 ug/day for men(1). A typical chloroform
level in soft drinks is about 23 ug/l(1). For an avg soft drink intake of 289
ml/day, this corresponds to a chloroform
intake of about 6 ug/day(1). Limited data on levels of trihalomethanes
(including chloroform) in food suggest
that the additional intake from other foods and dairy products will be small(1).
Thus, total intake from food and beverages appears to be approximately 10 ug/day
for someone who drinks an avg amount of soft drinks(1).
Body Burden:
Old Love Canal, Niagara Falls, NY - 9
individuals: breath 3.9-95 ug/cu m, 26 ug/cu m median; blood 1.1-3.0 ng/ml, 1.6
ng/ml median; urine 460-1500 ng/l, 860 ng/l median(1). England - 8 individuals:
body fat 5-68 ppb; var organs 1-10 ppb(2); US - 4 urban sites: mothers' milk 7
of 8 samples pos, detected, not quantified(3).
The largest existing data set on chloroform
concns in the body has been provided by the TEAM Study measurements of exhaled
breath(1). About 800 people provided more than 1250 breath samples with mean
concns generally in the range of 0.5-3 ug/cu m with generally lower levels in
California compared with other sites (New Jersey, Maryland, North Dakota, and
North Carolina)(1). In a study of 163 people at indoor swimming pools, exposed
individuals had a mean chloroform
concn in the higher alveolar of 83 ug/cu m(1). Breath exposures were also
studied from a single subject who swam for 30 mins on 3 occasions, rested in the
water for the same length of time on one occasion and stayed near the pool but
out of the water for 30 mins on the final occasion(1). Pre-exposure breath
concns were less than 2 ug/cu m on all occasions, rising to 15 to 25 ug/cu m 2.5
mins after completing the swimming periods, but only to 11 mg/cu m after the
poolside exposure period(1). A study of chloroform
found in blood revealed that out of 979 people sampled between 1988-1992, the
mean chloroform concn was 0.0444 ng/ml(1).
This suggests that a large percentage of the U.S. population is exposed to chloroform,
but that very large exposures are rare(1). Chloroform
was also detected in 40 out of 42 breast milk samples at levels ranging from 0.1
to 65 ng/ml from nursing mothers in two New Jersey hospitals and from three
other hospitals in Pennsylvania, Louisiana, and West Virginia(1).
Average Daily Intake:
... Although data are scarce, maximum exposure
/to chloroform/ due to ingestion of
food has been estimated at 0.04 mg/day.
Natural Pollution Sources:
Chloroform
has been shown to occur naturally in the environment. For example, it is
produced by the tropical red algae Asparagopsis armata, and by the red seaweed,
A. taxiformis(1). It has been estimated that the mass of biogenic chloroform
exchanged to the atmosphere from tropical oceans is 350X10+3 tons/yr(1). Another
source of naturally occurring chloroform
has been reported in peat bogs(2). Samples taken from a bog located in Lower St.
Mary, New Brunswick, Canada in the fall of 1995 contained chloroform
ranging from 1-2 ppm(2).
Artificial Pollution Sources:
Emissions from its production and indirect
production (in the manufacture of ethylene dichloride); chlorination of drinking
water, municipal sewage, cooling water in electric power generating plants;
produced during the atmospheric photodegradation of trichloroethylenes; auto
exhaust; from its use as an extractant or solvent, chemical intermediate, dry
cleaning agent, fumigant ingredient, in fluorocarbon 22 production, synthetic
rubber production (1-2).
Chloroform's
production and use in the synthesis of hydrochlorofluorocarbon 22 (HCFC-22)(1)
may result in its release to the environment through various waste streams. Chloroform
is also released into the environment by the chlorination of drinking or
waste-water(2,3). Hypochlorous acid is formed during chlorination which reacts
with organic precursors forming chloroform(3).
Another source of chloroform is from
the use of household liquid bleach containing sodium hypochlorite(3). Some
researchers calculated the total mass of sodium hypochlorite used in bleach in
the U.S. in 1984 to be about 150 million lbs(3). Using an emission factor of
0.00168 lb chloroform produced per
pound of chlorine equivalent, the researchers calculated total emissions of chloroform
annually in the South Coast basin to be 5.3 tons which would be the equivalent
of about 100 tons nationwide(3). Chloroform
has also been detected as a contaminant in products including stain removers,
spot removers, correction fluid, fabric softeners and rodenticides(3). Of 19
building materials and other products used in a new building, four emitted chloroform:
two insecticides, a rodenticide and a scouring powder(3). Swimming pools have
also shown to be important sources of chloroform
due to their repeated chlorination(3).
Environmental Fate:
TERRESTRIAL FATE: Based on a classification
scheme(1), a Koc value ranging from 153-196(2,3) indicates that chloroform
is expected to have moderate mobility in soil(SRC). Volatilization of chloroform
from moist soil surfaces is expected to be an important fate process(SRC) given
a Henry's Law constant of 3.67X10-3 atm-cu m/mole(4). The potential for
volatilization of chloroform from dry
soil surfaces may exist(SRC) based upon a vapor pressure of 197 mm Hg(4). In a
study of chloroform residence time in
soils, chloroform was found to have a
half-life of 0.3 days when applied 1 cm deep into soil and 1.4 days when applied
10 cm deep(5). It was also classified as a "very short-lived" chemical
in soil matrices primarily due to its high volatility(5). Under normal
environmental conditions, chloroform
is not expected to undergo biodegradation in soils. However, several studies
have demonstrated that at low concns, chloroform
can be anaerobically degraded by methanogenic bacteria in the presence of a
primary substrate such as acetic acid(6) and even better under sulfate reducing
conditions(7).
AQUATIC FATE: Based on a classification
scheme(1), a Koc value ranging from 153-196(2,3) indicates that chloroform
is not expected to adsorb to sediment and suspended solids in water(SRC).
Volatilization from water surfaces is expected(3) based upon a Henry's Law
constant of 3.67X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an
estimation method(3), volatilization half-lives for a model river and model lake
are 1.3 hrs and 4.4 days, respectively(SRC). In a field study of chloroform
volatilization, it was found that the volatilization half-life from the Rhine
River was 1.2 days while in a lake located in the Rhine basin the half-life was
31 days(5). In another study, chloroform
from a municipal treatment plant injected into an estuarine arm of Chesapeake
Bay entirely disappeared within 4 km in the spring and within 11 km in winter
under ice(6). The decrease in concn could not be entirely due to dilution(6). Chloroform
was found to have a maximum water-to-air flux from an estuary of 350 tons/year
based on its Henry's Law constant and diffusion(7). Based on available
experimental data, aquatic degradation and transfer to the biotic mass or into
the aquatic sediment are not expected to be major removal mechanisms for chloroform(7).
The major process to be considered in the study of fate processes for chloroform
is the diffusive air/water exchange(7). Biodegradation of chloroform
in environmental aqueous environments is not well understood. Various reports
have both supported and refuted anaerobic biodegradation in water(8). According
to a classification scheme(9), a BCF ranging from 2.9-10.35(7) suggests the
potential for bioconcentration in aquatic organisms is low. Although base
catalyzed hydrolysis is expected to occur, the estimated rate constant of
6.4X10-5 L/mol-sec predicts that this will not be an environmentally important
degradation process(10).
ATMOSPHERIC FATE: According to a model of
gas/particle partitioning of semivolatile organic compounds in the
atmosphere(1), chloroform, which has a
vapor pressure of 197 mm Hg at 25 deg C(2), is expected to exist solely as a
vapor in the ambient atmosphere. Vapor-phase chloroform
is degraded in the atmosphere by reaction with photochemically-produced hydroxyl
radicals(SRC); the half-life for this reaction in air is estimated to be 151
days(SRC), calculated from its rate constant of 1.03X10-13 cu cm/molecule-sec at
25 deg C(3). The tropospheric half-life for chloroform
has been estimated at 3 yrs(4).
Environmental Biodegradation:
There are conflicting data on the
biodegradation of chloroform. Slow but
substantial biodegradation apparently can occur when the proper microbial
populations exist and are acclimated to the chemical(10). Under aerobic
conditions, some investigators report little or no degradation in up to 25 wk
(1,2,3) while others report considerable degradation: 49% in 7 days, 100% in 28
days; however, a large fraction of this loss was due to volatilization (4); 25%
in 14 days(5), and 67% in 24 days(6). Under anaerobic conditions, slow
degradation has been reported after acclimation(7) and degradation was reported
in river bank (31% in <1 yr) and dune (100% in <3 mo) infiltration(8).
However, another investigator reported no degradation in 27 weeks in aquifer
material in the laboratory(9).
AEROBIC: No marine biodegradation of CHC (chlorohydrocarbons
including chloroform) has been
reported(1). Chloroform, present at
100 mg/l, reached 0% of its theoretical BOD in 2 weeks using an activated sludge
inoculum at 30 mg/l and the Japanese MITI test(2). Among the aerobic
microorganisms, chloroform has been
shown to be degradable only by methanotrophic bacteria(3). When it is introduced
into an aerobic bioreactor for treatment, it appears in the effluent and is not
degraded(3). The disappearance of chloroform
from a wastewater treatment plant was studied(4). At an air/water flow rate of
0.10 cu cm/cu m min, chloroform, at an
initial concn of 43.3 ug/l had an avg effluent concn of 3.6 ug/l with 32.5%
being air stripped and 59.2% being degraded(4).
ANAEROBIC: Chloroform
can be biodegraded under anaerobic conditions(1). Several studies have
demonstrated that at low concns, chloroform
can be anaerobically degraded by methanogenic bacteria in the presence of a
primary substrate such as acetic acid(1). When a batch study was conducted using
a mixed methanogenic culture at 35 deg C, chloroform
underwent complete biodegradation from an initial concn of 0.34 uM soln using
acetic acid as the primary substrate(1). It has also been reported that chloroform
underwent 96% degradation at an initial concn of 0.28 uM in a continuous-flow
fixed film methanogenic column which was fed acetic acid as the primary
substrate(1). A limiting factor in the anaerobic biodegradation of chloroform
is the initial concn(1). Chloroform
has been shown to have an inhibitory effect on degradation at concns as low as
1.67 uM(1). However, under sulfate reducing environments, chloroform
was found to not have such an inhibitory effect on the microorganisms(2). Even
at an initial concn of 22.6 uM, 96% of chloroform
was reduced by sulfate reducing organisms(2). Rates of transformation by the
suflate-reducing culture was found to be much higher than the rates observed for
an acetic acid utilizing methanogenic culture(2). The culture degraded chloroform
primarily by reductive dehalogenation leading to the formation of an equimolar
amount of dichloromethane, which was degraded at a very slow rate compared to chloroform(2).
Additional acclimation of the culture for 1 year did not lead to any appreciable
change in the rate of transformation of chloroform(2).
Environmental Abiotic Degradation:
The rate constant for the vapor-phase reaction
of chloroform with photochemically-produced
hydroxyl radicals has been estimated as 1.03X10-13 cu cm/molecule-sec at 25 deg
C(1). This corresponds to an atmospheric half-life of about 151 days at an
atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). Some studies have
shown that chloroform has an
atmospheric half-life of 80 days with reaction with hydroxyl radicals which
amounts to a 0.9% loss per sunlit day(2,3). Chloroform
is more reactive in photochemical smog situations (presence of NOx) with an avg
degradation rate of 0.8%/hr(4). A base-catalyzed second-order hydrolysis rate
constant of 6.5X10-5 L/mole-sec(SRC) was estimated using a structure estimation
method(5); this corresponds to half-lives of 3400 and 340 yrs at pH values of 7
and 8, respectively(5). Based on this estimation, base catalyzed hydrolysis is
not expected to be environmentally important degradation process(SRC). Another
study has determined a hydrolysis half-life of 1850 yrs at 25 deg C and pH 7(6).
Under oxidative degradation, chloroform
has been shown to produce phosgene, hydrogen chloride, water, carbon dioxide and
chlorine(7). Chloroform decomposes at
ordinary temperature in sunlight in the absence of air, and in the dark in the
presence of air(8). Photodegradation does not appear to be a significant loss
process in aquatic systems(9).
Environmental Bioconcentration:
Little or no tendency to bioconcentrate; log
bioconcentration factor <1 for 4 species of fish(1,2).
The BCF values for chloroform
range from 2.9-10.35(1). According to a classification scheme(2), these BCF
values suggest the potential for bioconcentration in aquatic organisms is low.
In another paper, an experimental log BCF of 0.78 was reported further
supporting its low potential for bioconcentration(3).
Soil Adsorption/Mobility:
Chloroform
is adsorbed most strongly to peat moss, less strongly to clay, very slightly to
dolomite limestone and not at all to sand(1). The Koc values measured for 2
soils was 34; however, 3 other soils with the lowest organic carbon content in
the same study gave no appreciable adsorption(3). Field experiments in which chloroform
was injected into an aquifer and the concentration in a series of observation
wells determined, demonstrated that chloroform
is very poorly retained by aquifer material (retardation factor 2-4), less so
than other C1- and C2-halogenated compounds studied(2,3). Laboratory percolation
studies with a sandy soil gave similar results (retardation factor <1.5)(4).
A soil sorption study was conducted on chloroform
in three distinctly different soils(1). Soils used were from Missouri (composed
of 11.4% sand, 52.7% silt, 33.4% clay, 2.4% organic matter, at pH 6.9),
California (composed of 45.1% sand, 35.2% silt, 21.7% clay, organic matter 1.7%,
at pH 8.1), and Florida (composed of 91.7% sand, 6.3% silt, 2.0% clay, 1.6%
organic matter, at pH 4.7)(1). The ratio of the amount of contaminant adsorbed
in micrograms per gram of soil to the equilibrium concn in ppm was used to
calculate a Kd value of 2.133 in the Missouri soil, 1.941 in the California
soil, and 1.763 in the Florida soil(1). These values correspond to a Koc value
ranging from 153-196 based upon the relationship between Kd and Koc(2).The
observed sorption was primarily as a result of adsorption (soil-solute
interaction) forces rather than partitioning(1).
Volatilization from Water/Soil:
The Henry's Law constant for chloroform
is 3.67X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that chloroform
is expected to volatilize rapidly from water surfaces(2). Based on this Henry's
Law constant, the volatilization half-life from a model river (1 m deep, flowing
1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1.3 hrs(SRC). The
volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind
velocity of 0.5 m/sec)(2) is estimated as 4.4 days(SRC). Three laboratory
studies of the evaporation of chloroform
from water gave half-lives of 3-5.6 hrs with moderate mixing conditions(3-5). Chloroform's
Henry's Law constant(1) indicates that volatilization from moist soil surfaces
may occur(SRC). The potential for volatilization of chloroform
from dry soil surfaces may exist(SRC) based upon a vapor pressure of 197 mm
Hg(6).
Environmental Water Concentrations:
SEAWATER: Pacific Ocean <0.05 parts per
trillion (1); Northeast Atlantic Ocean 4-13 parts per trillion , avg 8 parts per
trillion (2); Point Reyes (near shore) 2.8 ppb(3). Gulf of Mexico 4-200 ppb(4).
DRINKING WATER: US Federal Survey of Finished
Waters find a 70.3% occurrence in drinking water from groundwater supplies(9);
30 Canadian Treatment Facilities (treated water) 35 ppb avg summer, 21 ppb avg
winter (93-97% pos, 110 ppb max - raw water had 2-6 ppb avg concn)(1); US 5 City
Survey 1-301 ppb(2); Drinking Water wells in NY and NJ 67-490 ppb(3); Other
cities report values between 0-190 ppb(4-7) with the values highest in summer
and lowest in winter(4) and increasing on contact with residual chlorine(7).
National Organic Reconnaissance Survey (80 US water supplies, 1975) 0-311 ppb,
National Organics Monitoring Survey (113 finished water supplies, 1976-1977)
32-68 ppb median of positive supplies, 92-100% pos(8).
DRINKING WATER: Chloroform
is prevalent in tap water throughout much of the country(1). About 50% of the
U.S. population uses chlorinated surface water and another 25% consume
chlorinated groundwater(1). In a study of 35 water utility plants(including 10
in California), median chloroform
levels in distributed water ranged from 9.6-15 ug/l by quarter(1). In another
study, chloroform concn was determined
in drinking water in Los Angeles from Feb 1987 to July 1987 at 6.8 ug/l and 11
ug/l, respectively(1). The mean concn of chloroform
in New Jersey drinking water avgd about 50 ug/l, ranging from 17 ug/l in the
winter of 1983 to 70 ug/l in the fall of 1981(1). Los Angeles had rather lower
levels of 14 and 29 ug/l in the winter and spring of 1984, and even lower levels
of 7 and 11 ug/l in winter and summer of 1987(1). Mean values were very low in
Devils Lake, ND (1.4 ug/l) because the water supplies were from private wells
and were not chlorinated(1). In a similar study, both treatment plant and tap
water samples from three community water systems were analyzed for chloroform
concn(1). Chloroform ranged from 11 to
100 ug/l at the plants and from 21 to 160 ug/l at the tap(1).
GROUNDWATER: Contaminated wells in NY and NJ
67-490 ppb(1); Groundwater in the Netherlands 5 ppb(2). Water samples taken from
50 different groundwater sources located within the state of Kansas had an avg chloroform
concn of 13.5 ug/l (range <0.1-91.2 ug/l)(3). Most of the samples were
collected between mar 7 and Apr 11, 1986(3).
SURFACE WATER: Ohio River Basin (1980-81, 11
stations, 4972 samples) 72% pos, 832 samples 1-10 ppb, 27 samples >10 ppb(1).
14 Heavily Industrialized River Basins in US (204 sites) 1-120 ppb, 79% pos(2).
US - 5 industrial cities 9-31 ppb avg, 394 ppb max(3). 11 Water Utilities on
Ohio River 0.8 ppb avg, 4.8 ppb max, 68% pos(4); Delaware River and tributaries
- 30 sites 93% of samples >1 ppb(5); Ohio River and tributaries 232 samples
0.1-22 ppb, 72% pos(6); Lakes Erie, Michigan and Huron 1-30 ppb, 11 of 13 sites
pos(7).
SURFACE WATER: Various estuaries were studied
for the concns of several pollutants. From 1987-89, chloroform
was detected in the Scheldt, Netherlands/Belgium estuary ranging from
<10-1640 ng/l whereas in 1993, it was detected at 42.6 ng/l(1). In 1992, chloroform
was detected in the Humber, Tees, Tyne, Wear, and Tweed estuaries (all located
in the U.K.) ranging from <10-16.2, <10-11,500, <10-239, <10-199,
and <10 ng/l, respectively(1). In 1990, chloroform
was detected in the Forth (U.K.) and Rhine (Netherlands) estuaries ranging from
<500 and 3-10 ng/l, respectively(1). From 1987-89, chloroform
was detected in the Mersey(U.K.) estuary ranging from 200-5,200 ng/L(1). In
February and May of 1977, chloroform
was detected in Back River (U.S.A.) ranging from <120-49000 and 120-12500 ng/l,
respectively(1). The main factor determining the estuarine VOC concn is the
proximity of industrial sites(1). Chloroform
was also detected in fjord waters at Stenungsundfjorden (Sweden) in 1988 ranging
from 5.4-14.8 ng/l and in shelf sea waters off the Belgian Continental Shelf in
1993 ranging from 11.3-17.4 ng/l(1). In August 1972, chloroform
concns in the North East Atlantic were measured ranging from 4-13 ng/l(1).
RAIN/FOG/SNOW: Detected in rain and snow in
Japan(1,2) and 250 parts per trillion rain in West Los Angeles(3). Chloroform
concns in clouds was investigated from samples collected above the canopy of a
coniferous forest during several days between May and October 1987 and May and
July 1988 at Mt. Mitchell State Park, NC(4). The avg concn detected in the cloud
water samples was 2.41 ng/ml (range 0-10 ng/ml) while avg air concns were 1.19
ng/l and avg rain concns 241 ng/l(4). The deposition via clouds was estimated to
be 1.27X10+6 ng/sq m yr(4).
Effluent Concentrations:
Rubber and chemical companies - Louisville, KY
22 ppm max(1). Industries whose wastewater levels of chloroform
exceed a mean level of 500 ppb are auto and other laundries, aluminum forming,
pharmaceuticals, and pulp and paper mills; the pharmaceutical industry
contributes the largest amount of chloroform
with mean and max wastewater concn of 49 and 280 ppb, respectively (2). Auto
exhausts typically 27 ug/cu m(1).
Chloroform
was detected at 245 ppm in the gas effluent emitted from a Municipal Landfill
Site (MLS) in Palos Verdes, CA(1). A study of compounds found in automobile
exhaust revealed that chloroform was
not present(2). During the chlorite bleaching of kraft pulp, a variety of
organic chlorinated compounds can be formed(3). Of these, chloroform
has been found to be the main volatile organochlorine compound formed(3). The
effluent from a kraft pulp mill using chlorite bleaching prior to treatment and
the effluent following activated sludge waste water treatment revealed chloroform
concns at 180 and 34 ug/l, respectively(3). At another mill, concns before and
after treatment were 6.2 and 1.6 ug/l while at a third mill concns were 16 ug/l
and not detected(3). In 1993, the Toxic Release Inventory (TRI) System reported
that 175 facilities had emissions of 13.8 million lb of chloroform
to air, another 450,000 lb to water, and 70,000 lb to land(4). The facilities
with the largest emission (100,000 to 700,000 lb) were pulp and paper plants(4).
Sediment/Soil Concentrations:
Not detected in sediment at an industrial
location on US river(1). Not detected in Back River sediment off Baltimore(2).
Atmospheric Concentrations:
URBAN/SUBURBAN: Airborne concns and sources of
chloroform were evaluated in two urban
areas in Illinois: southeast Chicago and East St. Louis between May 1986-April
1990(1). The avg concn of chloroform
found in 103 air samples from Chicago was 0.3 ug/cu m (max 1.6 ug/cu m) and from
83 air samples from East St. Louis was 0.5 ug/cu m (max 6.6 ug/cu m)(1). The
contribution of chloroform to
Chicago's atmosphere was due to both waste water treatment and chemical plant
emissions(1). The Illinois Department of Energy and Natural Resources estimate
that Southeast Chicago contributes 12 tons of chloroform
per year while East St. Louis contributes 9 tons/year(1). Twelve hour avg
outdoor concns of chloroform in
California (from 1984-1987) ranged from 0.2 to 0.6 ug/cu m while outdoor air
concns in New Jersey (from 1981-1983) ranged from 0.1 to 1.5 ug/cu m(2). In
another study of air from Los Angeles, CA, 2,251 24-hr air samples had an avg
concn of 0.16 ug/cu m between the years 1986-1991(2). Outdoor air measurements
made in chemical manufacturing areas sometimes show higher chloroform
values(2). Studies in the Kanawha Valley from 1986-1988 indicated mean outdoor
concns of 11.5 ug/cu m near a major chemical manufacturing facility in Belle,
WV(2). Mean values of 3 ug/cu m were observed at two other sites (Institute, WV
and South Charleston, WV)(2). Compared to mean personal exposures of indoor air
concns, these outdoor values are often lower by factors of 2 to 8(2).
INDOOR: Studies have shown that chloroform
in indoor air was present at four to five times the outdoor air level, and that
levels could be higher still in the shower(1). Subsequent studies verified that
inhalation exposure during showers might be comparable to ingestion of 1 to 6 L
of drinking water a day(1). Mean indoor air concns of chloroform
over 12 hr periods during June 1987 in Los Angeles, CA were found to be 1.4 ug/cu
m at night in the kitchen, 1.1 ug/cu m during the day in the kitchen and 0.90
during the day in the living room(1). In another study, chloroform
concns in air from a shower using water from a municipal water supply revealed
that chloroform concns increased from
2 to 100 ppb (10 to 500 ug/cu m) during the 10 minute shower(1). In a similar
study, 19 10-minute showers using water at 40 deg C and chloroform
concns ranging from 12.9 to 40.0 ug/l resulted in air concns in the shower stall
ranging from 69-327 ug/cu m(1). The ultimate source of most of the chloroform
in indoor air in most homes is evaporation from chlorinated water(1). Major uses
of water in the home include showers, baths, clothes washing and dish
washing(1). Several studies of indoor swimming pools indicate that inhalation
can provide substantial amounts of chloroform(1).
US RURAL/REMOTE - 532 samples 40 parts per
trillion avg(1); Northern Hemisphere - background 17.1 parts per trillion avg(2)
US URBAN/SUBURBAN - 1739 samples, 72 parts per trillion avg(1); US SOURCE
DOMINATED AREAS - 306 samples, 820 parts per trillion avg(1). 11 highly
industrialized US locations, 0-10.9 ppb(3); 10 US cities 32-703 parts per
trillion avg, 5112 parts per trillion max(4-6); 3 areas in NJ, 710 parts per
trillion avg, 15% pos avg of pos samples approx 4 ppb(7).
RURAL/REMOTE: Rural air samples near
Champaign, IL (8 km south of Bondville, IL) were studied from February 1987 to
April 1990 for various volatile organic compounds(1). The avg concn of chloroform
found in 23 air samples was 0.3 ug/cu m (max 0.4 ug/cu m)(1). There were no
point sources within 10 km and the site was at least 50 km downwind of urban
areas during times of prevailing winds(1).
Food Survey Values:
In pilot market basket survey of 4 food groups
at 5 sites, the results for chloroform
were: dairy composite 17 ppb (1 of 5 sites), meat composite - not detected; oil
and fat composite - trace (1 of 5 sites); beverage composite 6-32 ppb (4 of 5
sites); high values for individual foods were soft drinks 9-178 ppb; butter 56
ppb; cheese 15-17 ppb; mayonaise 34 ppb(1). England: various samples of food
including dairy products, eggs, bread, meat, oils and fats, beverages, fruits
and vegetables 0.4-33 ppb, cheese, butter and tea were high(2). Residues were
found in fumigated sorghum, barley and corn but generally disappeared within 60
days when aired at 17 deg C(3).
A pilot study was conducted in 1980 to measure
chloroform in five "Market
Basket" food samples collected from grocery stores in New Jersey, North
Carolina, and Washington, D.C.(1). Chloroform
concns in cola soft drinks avgd 49 ug/l while in non-cola soft drinks 11 ug/l(1).
A typical chloroform level in soft
drinks is about 23 ug/l(1). One of the five dairy composites also contained chloroform:
milk and cheese avgd 4 ng/g and one butter samples contained 12 ng/g(1). Ice
cream and mayonnaise also contained chloroform
at 12 and 23 ng/g, respectively(1). Another FDA study of VOCs in margarines
detected chloroform in 5 of 18 samples
collected at stores and in 13 of 19 finished products collected at manufacturing
plants(1). The levels were much higher at the manufacturing plants than in the
stores, with two samples between 100 and 150 ng/g and ten others between 15 and
50 ng/g. It was later determined that VOCs migrated from the packaging glues
into the margarine(1). In a study of 18 table-ready food items, ten contained chloroform
with the highest levels occuring in butter 670 ng/g, Cheddar cheese 80 ng/g,
granola 57 ng/g, and peanut butter 29 ng/g(1). Mean values of 14 samples of
butter was 364 ng/g; 8 samples of cheese 182 ng/g; 11 samples of cereal 60 ng/g;
7 samples of peanut butter 51.3 ng/g; and 12 samples of highly processed foods
122 ng/g(1). The sources of chloroform
in food are not clearly understood however migration of chloroform
from packaging solvents, glues, and inks has been documented(1).
Fish/Seafood Concentrations:
Great Britain: various species of marine fish
5-851 ppb(1,2); marine invertebrates 2-1040 ppb(1,2).
Animal Concentrations:
England: grey seal 7.6-22 ppb (blubber), 0-12
ppb (liver); marine and freshwater birds 0.7-65 ppb(1).
Milk Concentrations:
US - 4 urban sites: mothers' milk 7 of 8
samples pos detected, not quantified.
A study of human milk and pasteurized and
unpasteurized cow's milk from a suburban area of Turku, Finland was conducted to
determine possible chloroform
levels(1). Chloroform concns in
pasteurized cow's milk ranged from undetectable to 3.1 ug/l while chloroform
was not detected in either human or unpasteurized cow's milk(1).
Environmental Standards & Regulations:
TSCA Requirements:
Pursuant to section 8(d) of TSCA, EPA
promulgated a model Health and Safety Data Reporting Rule. The section 8(d)
model rule requires manufacturers, importers, and processors of listed chemical
substances and mixtures to submit to EPA copies and lists of unpublished health
and safety studies. Chloroform is
included on this list.
CERCLA Reportable Quantities:
Persons in charge of vessels or facilities are
required to notify the National Response Center (NRC) immediately, when there is
a release of this designated hazardous substance, in an amount equal to or
greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number
of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202)
426-2675. The rule for determining when notification is required is stated in 40
CFR 302.4 (section IV. D.3.b).
Releases of CERCLA hazardous substances are
subject to the release reporting requirement of CERCLA section 103, codified at
40 CFR part 302, in addition to the requirements of 40 CFR part 355. Chloroform
is an extremely hazardous substance (EHS) subject to reporting requirements when
stored in amounts in excess of its threshold planning quantity (TPQ) of 10,000
lbs.
RCRA Requirements:
U044; As stipulated in 40 CFR 261.33, when chloroform,
as a commercial chemical product or manufacturing chemical intermediate or an
off-specification commercial chemical product or a manufacturing chemical
intermediate, becomes a waste, it must be managed according to Federal and/or
State hazardous waste regulations. Also defined as a hazardous waste is any
residue, contaminated soil, water, or other debris resulting from the cleanup of
a spill, into water or on dry land, of this waste. Generators of small
quantities of this waste may qualify for partial exclusion from hazardous waste
regulations (40 CFR 261.5).
D022; A solid waste containing chloroform
may or may not become characterized as a hazardous waste when subjected to the
Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so
characterized, must be managed as a hazardous waste.
Atmospheric Standards:
This action promulgates standards of
performance for equipment leaks of Volatile Organic Compounds (VOC) in the
Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect
of these standards is to require all newly constructed, modified, and
reconstructed SOCMI process units to use the best demonstrated system of
continuous emission reduction for equipment leaks of VOC, considering costs, non
air quality health and environmental impact and energy requirements. Chloroform
is produced, as an intermediate or a final product, by process units covered
under this subpart.
Listed as a hazardous air pollutant (HAP)
generally known or suspected to cause serious health problems. The Clean Air
Act, as amended in 1990, directs EPA to set standards requiring major sources to
sharply reduce routine emissions of toxic pollutants. EPA is required to
establish and phase in specific performance based standards for all air emission
sources that emit one or more of the listed pollutants. Chloroform
is included on this list.
Chloroform
has been designated as a hazardous air pollutant under section 112 of the Clean
Air Act.
Clean Water Act Requirements:
Based on the consumption of 2 l of drinking
water and consumption of 6.5 g of fish and shellfish, the corresponding cancer
risk levels and criteria are 1X10-7: 0.019 ug/l; 1X10-6: 0.19 ug/l; 1X10-5: 1.90
ug/l. Based on consumption of fish and shellfish only, the corresponding cancer
risk levels and criteria are 1X10-7: 1.57 ug/l; 1X10-6: 15.7 ug/l; 1X10-5: 157
ug/l.
Toxic pollutant designated pursuant to section
307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent
limitations.
Chloroform
is designated as a hazardous substance under section 311(b)(2)(A) of the Federal
Water Pollution Control Act and further regulated by the Clean Water Act
Amendments of 1977 and 1978. These regulations apply to discharges of this
substance. This designation includes any isomers and hydrates, as well as any
solutions and mixtures containing this substance.
The maximum contaminant level (MCL) set forth
by the National Primary Drinking Water Regulations for organic chemicals
including total trihalomethanes (the sum of the concentrations of
bromodichloromethane, dibromochloromethane, tribromomethane (bromoform) and trichloromethane
(chloroform)) is 0.10 mg/l. /Total
trihalomethanes/
Federal Drinking Water Standards:
EPA 80 ug/l
State Drinking Water Guidelines:
(AZ) ARIZONA 0.49 ug/l
(FL) FLORIDA 6 ug/l
(MA) MASSACHUSETTS 5 ug/l
(MN) MINNESOTA 60 ug/l
(NH) NEW HAMPSHIRE 6.0 ug/l
(WI) WISCONSIN 6 ug/l
FDA Requirements:
FDA BANNED USE OF CHLOROFORM
AS INGREDIENT (ACTIVE OR INACTIVE) IN HUMAN DRUG & COSMETIC PRODUCTS AS OF
JULY 29, 1976.
Chloroform
is an indirect food additive for use only as a component of adhesives.
Chemical/Physical Properties:
Molecular Formula:
C-H-Cl3
Molecular Weight:
119.38
Color/Form:
Clear, colorless liquid
Colorless, highly refractive, heavy volatile
liquid.
Odor:
Pleasant, etheric, nonirritating
Pleasant odor.
Odor threshold: 205-307 ppm
Taste:
Sweet taste
Boiling Point:
61.2 deg C
Melting Point:
-63.2 deg C
Corrosivity:
Liquid chloroform
will attack some forms of plastics, rubber, and coatings.
Critical Temperature & Pressure:
Critical temperature: 506 deg F= 263.2 deg C=
536.4 K; Critical pressure: 790 psia= 54 atm= 5.5 Mn/sq m
Density/Specific Gravity:
Specific gravity: 1.4835 @ 20 deg C/20 deg C
Heat of Combustion:
Not pertinent
Heat of Vaporization:
106.7 BTU/lb= 59.3 cal/g= 2.483X10+5 J/kg
Octanol/Water Partition Coefficient:
log Kow= 1.97
Solubilities:
Sol in carbon disulfide
Water solubility = 7,710 mg/l at 25 deg C
Miscible with alcohol, ether, benzene, carbon
tetrachloride, fixed and volatile oils.
In water, 3.81 g/kg @ 25 deg C
Spectral Properties:
[Lillian D et al; Environ Sci Technol 9:
1042-8 1975) as cited in USEPA; Water-Related Environ Fate of 129 Priority
Pollutants p.40-2 (1979) USEPA 440/4-79-0296] Absorbs UV maximally at 175 nm
SADTLER REF NUMBER: 2224 (IR, PRISM)
Index of refraction: 1.4422 @ 25 deg C/D
IR: 305 (Sadtler Research Laboratories IR
Grating Collection)
NMR: 10513 (Sadtler Research Laboratories
Spectral Collection)
MASS: 445 (Atlas of Mass Spectral Data, John
Wiley & Sons, New York)
Intense mass spectral peaks: 83 m/z, 118 m/z
Surface Tension:
27.1 dynes/cm= 0.0271 N/M @ 20 deg C
Vapor Density:
4.12 (Air= 1)
Vapor Pressure:
197 mm Hg at 25 deg C
Relative Evaporation Rate:
11.6 (butyl acetate= 1)
Viscosity:
5.63 millipoises at 20 deg C; 5.10 millipoises
at 30 deg C
Other Chemical/Physical Properties:
Liquid-Water Interfacial Tension: 32.8
dynes/cm= 0.0328 N/m at 20 deg C
Ratio of specific heats of vapor: 1.146
Weight per gallon at 25 deg C: 12.29 lb
Partition coefficients at 25 deg C for chloroform
into blood= 8.4; into oil= 394.
Ionization potential: 11.42 eV
Heat of fusion: 17.62 cal/g
Heat capacity @ 20 deg C: 0.979 kJ/kg.K;
critical density: 500 kg/cu m; critical vol: 0.002 cu m/kg; thermal conductivity
@ 20 deg C: 0.130 W/m.K; coefficient of cubical expansion: 0.001399; dielectric
constant @ 20 deg C: 4.9; dipole moment: 3.84X10-30 C.m; heat of formation @ 25
deg C: -89.66 MJ/kg.mole (gas), -120.9 MJ/kg.mole (liq); latent heat of
evaporation @ bp: 247 kJ/kg
The azeotrope with water boils @ 56.1 deg C
and contains 97.2% chloroform. The
ternary azeotrope with ethanol and water boils @ 55.5 deg C and contains 4 mol%
alcohol and 3.5 mol% water. At 25 deg C, chloroform
dissolves 3.59 times its volume of carbon dioxide.
Chloroform
forms azeotropes with acetone, 2-bromopropane, 2-butanone, ethanol, ethyl
formate, formic acid, n-hexane, isopropanol, methanol, methyl acetate, and
water.
Mobile liquid
Vapor pressure= 100 mm Hg @ 10.4 deg C
Henry's Law constant = 3.67X10-3 atm-cu m/mol
at 24 deg C
Hydroxyl radical rate constant= 1.03X10-13 cu
cm/molecule-sec @ 25 deg C
Chemical Safety & Handling:
Hazards Summary:
The major hazards encountered in the use and
handling of chloroform stem from its
toxicologic properties. Toxic effects may be exerted from all routes of exposure
(ie, ingestion, dermal, or inhalation). Aside from possible contact burns or
irritation to the skin and eyes, the range of acute effects from exposure to chloroform
include dizziness, headache, nausea, CNS depression, cardiac arrhythmia, and
death. Chronic exposure may result in damage (sometimes fatal) to the liver and
kidneys. OSHA has set the PEL at 50 ppm, while the ACGIH recommends a TLV of 10
ppm. These levels notwithstanding, contact with chloroform
also should be protected against by wearing impervious clothing (PVC and rubber
are not suitable), and a full facepiece self-contained breathing apparatus
operated in positive pressure mode. Non-impervious clothing which becomes wet
with chloroform should be promptly
removed and any contaminated skin washed with soap and water. Only authorized
personnel should be permitted in areas where chloroform
exposure may occur. Chloroform will
not ignite easily, but it may burn with the emission of highly toxic (eg,
phosgene) and irritating gases. If chloroform
is involved in a fire, extinguish the fire using an agent suitable for the type
surrounding material. Wear protective equipment as stated above. Fire-control
water should be diked, as necessary, to prevent chloroform
from entering water sources and sewers. Chloroform
reacts explosively with chemically-reactive metals (eg, aluminum or magnesium
powder, sodium, and lithium), strong oxidizers, and strong caustics (eg,
alkalis), and decomposes in sunlight. Therefore, chloroform
should be stored away from such materials and in a dark, cool, dry,
well-ventilated areas. While chloroform
has a pleasant, etheric odor, this clear, colorless liquid also has the ability
to cause olfactory fatigue and, therefore, warning of its presence is not
assured. For this reason, and because its decomposition by prolonged exposure to
air can result in accumulation of phosgene, chloroform
should be kept in tightly closed containers affixed with the label,
"Poison". Containers may be transported by air, rail, road, or water.
Small spills of chloroform should be
absorbed with vermiculite, dry sand, or earth and collected for disposal. Large
land spills should be diked (eg, with soil or sand bags) and the bulk liquid
absorbed (eg, with fly ash or cement powder), or contained in an excavated pit,
pond, or other holding area that has been sealed with an impermeable flexible
membrane liner. Spills of chloroform
in bodies of water may first need to be trapped at the bottom with sand bag
barriers and treated with activated carbon. Trapped material is then removed by
suction hose, mechanical lifts, or dredges. Collected chloroform
is a candidate for liquid injection, rotary kiln, or fluidized bed incineration.
Before implementing any plans for permanent land disposal, consult with
environmental regulatory agencies.
DOT Emergency Guidelines:
Health: Highly toxic, may be fatal if inhaled,
swallowed or absorbed through skin. Avoid any skin contact. Effects of contact
or inhalation may be delayed. Fire may produce irritating, corrosive and/or
toxic gases. Runoff from fire control or dilution water may be corrosive and/or
toxic and cause pollution.
Fire or explosion: Non-combustible, substance
itself does not burn but may decompose upon heating to produce corrosive and/or
toxic fumes. Containers may explode when heated. Runoff may pollute waterways.
Public safety: CALL Emergency Response
Telephone Number. ... Isolate spill or leak area immediately for at least 25 to
50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away.
Stay upwind. Keep out of low areas.
Protective clothing: Wear positive pressure
self-contained breathing apparatus (SCBA). Wear chemical protective clothing
which is specifically recommended by the manufacturer. It may provide little or
no thermal protection. Structural firefighters' protective clothing provides
limited protection in fire situations ONLY; it is not effective in spill
situations.
Evacuation: ... Fire: If tank, rail car or
tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all
directions; also, consider initial evacuation for 800 meters (1/2 mile) in all
directions.
Fire: Small fires: Dry chemical, CO2 or water
spray. Large fires: Water spray, fog or regular foam. Move containers from fire
area if you can do it without risk. Dike fire control water for later disposal;
do not scatter the material. Use water spray or fog; do not use straight
streams. Fire involving tanks or car/trailer loads: Fight fire from maximum
distance or use unmanned hose holders or monitor nozzles. Do not get water
inside containers. Cool containers with flooding quantities of water until well
after fire is out. Withdraw immediately in case of rising sound from venting
safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in
fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is
impossible withdraw from area and let fire burn.
Spill or leak: Do not touch damaged containers
or spilled material unless wearing appropriate protective clothing. Stop leak if
you can do it without risk. Prevent entry into waterways, sewers, basements or
confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover
with dry earth, sand or other non-combustible material and transfer to
containers. DO NOT GET WATER INSIDE CONTAINERS.
First aid: Move victim to fresh air. Call 911
or emergency medical service. Apply artificial respiration if victim is not
breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the
substance; induce artificial respiration with the aid of a pocket mask equipped
with a one-way valve or other proper respiratory medical device. Administer
oxygen if breathing is difficult. Remove and isolate contaminated clothing and
shoes. In case of contact with substance, immediately flush skin or eyes with
running water for at least 20 minutes. For minor skin contact, avoid spreading
material on unaffected skin. Keep victim warm and quiet. Effects of exposure
(inhalation, ingestion or skin contact) to substance may be delayed. Ensure that
medical personnel are aware of the material(s) involved, and take precautions to
protect themselves.
Odor Threshold:
3.30 mg/l (Detection in air; purity not
specified)
Odor thresholds: low= 250 mg/cu m; high= 1000
mg/cu m. /From table/
Odor thresholds of 85 ppm and 2.4 ppm have
been reported for chloroform in air
and water, respectively.
Skin, Eye and Respiratory Irritations:
Skin and eye irritant
Threshold of irritation: 20480 mg/cu m
Fire Fighting Procedures:
If material involved in fire: Extinguish fire
using agent suitable for type of surrounding fire. (Material itself does not
burn or burns with difficulty.)
Toxic Combustion Products:
Liberates phosgene when heated or involved in
fire.
Hazardous Reactivities & Incompatibilities:
Mixtures with dinitrogen tetraoxide are
explosive when subjected to shock of 25 g TNT equiv or less.
Chloroform
and acetone interact vigorously & exothermally in presence of solid
potassium hydroxide or calcium hydroxide to form
1,1,1-trichloro-2-hydroxy-2-methylpropane. A laboratory incident involving the
bursting of a solvent residues bottle was attributed to this reaction.
A chloroform-methanol
mixture was put into a drum contaminated with sodium hydroxide. A vigorous
reaction set in, and the drum exploded. Chloroform
normally reacts slowly with sodium hydroxide owing to the insolubility of the
latter. The presence of methanol (or other solubilizer) increases the rate of
reaction by increasing the degree of contact between chloroform
and alkali.
OXIDIZED BY STRONG OXIDIZING AGENTS SUCH AS
CHROMIC ACID, WITH FORMATION OF PHOSGENE & CHLORINE GAS
Heating aluminum powder with carbon
tetrachloride-chloroform mixtures in
closed systems to 152 deg C may cause an explosion, particularly if traces of
aluminum chloride are present.
Contact of 1.5 g portions of the solid
potassium tert-butoxide with drops of liquid chloroform
caused ignition after 0 min, and with vapors of chloroform
caused ignition after 2 min.
Triisopropylphosphine reacts, when undiluted,
rather vigorously with chloroform.
Disilane ... reacts vigorously with
incandescence in contact with chloroform.
Chloroform
with various alkali metals is impact-sensitive as follows: weak explosion with
lithium; fairly strong with sodium; strong with potassium; and violent with
sodium-potassium.
A violent explosion occurs if a soln of
perchloric acid in chloroform is
poured on phosphorus pentoxide.
When 1 g of sodium hydroxide was added to a
mixture of 1 ml methanol and 1 ml chloroform,
an exothermic reaction occurred. Potassium hydroxide and other alkalies may
replace sodium hydroxide as a reactant.
Incompatible with dinitrogen tetraoxide,
fluorine, metals, or triisopropylphosphine.
CHLOROFORM
... EXPLODES WHEN IN CONTACT WITH ALUMINUM POWDER OR MAGNESIUM POWDER.
Strong caustics; chemically-active metals such
as aluminum or magnesium powder, sodium & potassium; strong oxidizers [Note:
When heated to decomposition forms phosgene gas].
Explosive reaction with sodium + methanol or
sodium methoxide + methanol. Mixtures with sodium or potassium are impact
sensitive explosives.
Hazardous Decomposition:
The products of oxidative breakdown include
phosgene, hydrogen chloride, chlorine, carbon dioxide, and water.
On prolonged heating with water @ 225 deg C,
decomp to formic acid, carbon monoxide, and hydrogen chloride occurs.
Immediately Dangerous to Life or Health:
NIOSH recommends that chloroform
be regulated as a potential human carcinogen.
Protective Equipment & Clothing:
When handling /chloroform/,
use safety glasses, self-contained breathing apparatus, protective clothing.
Note: Polyvinyl chloride and rubber are unsuitable materials for protective
clothing.
PRECAUTIONS FOR "CARCINOGENS": ...
Dispensers of liq detergent /should be available./ ... Safety pipettes should be
used for all pipetting. ... In animal laboratory, personnel should ... wear
protective suits (preferably disposable, one-piece & close-fitting at ankles
& wrists), gloves, hair covering & overshoes. ... In chemical
laboratory, gloves & gowns should always be worn ... however, gloves should
not be assumed to provide full protection. Carefully fitted masks or respirators
may be necessary when working with particulates or gases, & disposable
plastic aprons might provide addnl protection. ... Gowns ... /should be/ of
distinctive color, this is a reminder that they are not to be worn outside the
laboratory. /Chemical Carcinogens/
Personnel protection: ... Wear appropriate
chemical protective gloves, boots and goggles.
For chloroform
some data (usually from emmession tests) suggesting breakthrough times greater
than one hour are not likely for butyl rubber.
For chloroform
breakthrough times (usually significantly less) than one hour reported by
(normally) two or more tests for natural rubber, neoprene, neoprene/ natural
rubber, nitrile rubber (nitrile) polyethylene (PE), chlorinated polyethylene (CPE)
polyvinyl chloride (PVC).
For chloroform
breakthrough times greater than one hour reported by (normally) two or more
tests for polyvinyl alcohol (PVA) and viton.
Wear appropriate personal protective clothing
to prevent skin contact.
Wear appropriate eye protection to prevent eye
contact.
Eyewash fountains should be provided in areas
where there is any possibility that workers could be exposed to the substance;
this is irrespective of the recommendation involving the wearing of eye
protection.
Facilities for quickly drenching the body
should be provided within the immediate work area for emergency use where there
is a possibility of exposure. [Note: It is intended that these facilities
provide a sufficient quantity or flow of water to quickly remove the substance
from any body areas likely to be exposed. The actual determination of what
constitutes an adequate quick drench facility depends on the specific
circumstances. In certain instances, a deluge shower should be readily
available, whereas in others, the availability of water from a sink or hose
could be considered adequate.]
Recommendations for respirator selection.
Condition: At concentrations above the NIOSH REL, or where there is no REL at
any detectable concentration. Respirator Class(es): Any self-contained breathing
apparatus that has a full facepiece and is operated in a pressure-demand or
other positive-pressure mode. Any supplied-air respirator that has a full
facepiece and is operated in a pressure-demand or other positive-pressure mode
in combination with an auxiliary self-contained breathing apparatus operated in
pressure-demand or other positive-pressure mode.
Recommendations for respirator selection.
Condition: Escape from suddenly occurring respiratory hazards: Respirator
Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a
chin-style, front- or back-mounted organic vapor canister. Any appropriate
escape-type, self-contained breathing apparatus.
Preventive Measures:
Local exhaust as required to control TLV in
air.
Wash thoroughly after handling, avoid
breathing vapor, and avoid contact with eyes.
Eating and smoking should not be permitted in
areas where liquid chloroform is
handled, processed, or stored.
Skin that becomes wet with liquid chloroform
should be promptly washed or showered with soap or mild detergent and water to
remove any chloroform. Employees who
handle chloroform should wash their
hands thoroughly with soap and mild detergent and water before eating, or
smoking.
Where there is any possibility that employees'
eyes may be exposed to chloroform, an
eye-wash fountain should be provided within the immediate work area for
emergency use.
Areas in which exposure to chloroform
may occur should be identified by signs or other appropriate means, and access
to these areas should be limited to authorized persons.
Good industrial hygiene practices recommend
that engineering controls be used to reduce environmental concentrations to the
permissible level. However, there are some exceptions where respirators may be
used to control exposure. Respirators may be used when engineering and work
practice controls are not technically feasible, when such controls are in the
process of being installed, or when they fail and need to be supplemented.
Respirators may also be used for operations which require entry into tanks or
closed vessels, and in emergency situations. In addition to respirator
selection, a complete respiratory protection program should be instituted which
includes regular training, maintenance, inspection, cleaning, and evaluation.
Clothing wet with liquid chloroform
should be placed in closed containers for storage until it can be discarded or
until provision is made for the removal of chloroform
from the clothing. If the clothing is to be laundered or otherwise cleaned to
remove the chloroform, the person
performing the operation should be informed of chloroform's
hazardous properties.
Contact lenses should not be worn when working
with this chemical.
SRP: The scientific literature for the use of
contact lenses in industry is conflicting. The benefit or detrimental effects of
wearing contact lenses depend not only upon the substance, but also on factors
including the form of the substance, characteristics and duration of the
exposure, the uses of other eye protection equipment, and the hygiene of the
lenses. However, there may be individual substances whose irritating or
corrosive properties are such that the wearing of contact lenses would be
harmful to the eye. In those specific cases, contact lenses should not be worn.
In any event, the usual eye protection equipment should be worn even when
contact lenses are in place.
PRECAUTIONS FOR "CARCINOGENS":
Smoking, drinking, eating, storage of food or of food & beverage containers
or utensils, & the application of cosmetics should be prohibited in any
laboratory. All personnel should remove gloves, if worn, after completion of
procedures in which carcinogens have been used. They should ... wash ... hands,
preferably using dispensers of liq detergent, & rinse ... thoroughly.
Consideration should be given to appropriate methods for cleaning the skin,
depending on nature of the contaminant. No standard procedure can be
recommended, but the use of organic solvents should be avoided. Safety pipettes
should be used for all pipetting. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": In
animal laboratory, personnel should remove their outdoor clothes & wear
protective suits (preferably disposable, one-piece & close-fitting at ankles
& wrists), gloves, hair covering & overshoes. ... clothing should be
changed daily but ... discarded immediately if obvious contamination occurs ...
/also,/ workers should shower immediately. In chemical laboratory, gloves &
gowns should always be worn ... however, gloves should not be assumed to provide
full protection. Carefully fitted masks or respirators may be necessary when
working with particulates or gases, & disposable plastic aprons might
provide addnl protection. If gowns are of distinctive color, this is a reminder
that they should not be worn outside of lab. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": ...
Operations connected with synth & purification ... should be carried out
under well-ventilated hood. Analytical procedures ... should be carried out with
care & vapors evolved during ... procedures should be removed. ... Expert
advice should be obtained before existing fume cupboards are used ... & when
new fume cupboards are installed. It is desirable that there be means for
decreasing the rate of air extraction, so that carcinogenic powders can be
handled without ... powder being blown around the hood. Glove boxes should be
kept under negative air pressure. Air changes should be adequate, so that concn
of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS":
Vertical laminar-flow biological safety cabinets may be used for containment of
in vitro procedures ... provided that the exhaust air flow is sufficient to
provide an inward air flow at the face opening of the cabinet, &
contaminated air plenums that are under positive pressure are leak-tight.
Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown
across the working area towards the operator, should never be used ... Each
cabinet or fume cupboard to be used ... should be tested before work is begun (eg,
with fume bomb) & label fixed to it, giving date of test & avg air-flow
measured. This test should be repeated periodically & after any structural
changes. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS":
Principles that apply to chem or biochem lab also apply to microbiological &
cell-culture labs ... Special consideration should be given to route of admin.
... Safest method of administering volatile carcinogen is by injection of a soln.
Admin by topical application, gavage, or intratracheal instillation should be
performed under hood. If chem will be exhaled, animals should be kept under hood
during this period. Inhalation exposure requires special equipment. ... Unless
specifically required, routes of admin other than in the diet should be used.
Mixing of carcinogen in diet should be carried out in sealed mixers under fume
hood, from which the exhaust is fitted with an efficient particulate filter.
Techniques for cleaning mixer & hood should be devised before expt begun.
When mixing diets, special protective clothing &, possibly, respirators may
be required. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": When
... admin in diet or applied to skin, animals should be kept in cages with solid
bottoms & sides & fitted with a filter top. When volatile carcinogens
are given, filter tops should not be used. Cages which have been used to house
animals that received carcinogens should be decontaminated. Cage-cleaning
facilities should be installed in area in which carcinogens are being used, to
avoid moving of ... contaminated /cages/. It is difficult to ensure that cages
are decontaminated, & monitoring methods are necessary. Situations may exist
in which the use of disposable cages should be recommended, depending on type
& amt of carcinogen & efficiency with which it can be removed. /Chemical
Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": To
eliminate risk that ... contamination in lab could build up during conduct of
expt, periodic checks should be carried out on lab atmospheres, surfaces, such
as walls, floors & benches, & ... interior of fume hoods & airducts.
As well as regular monitoring, check must be carried out after cleaning-up of
spillage. Sensitive methods are required when testing lab atmospheres. ...
Methods ... should ... where possible, be simple & sensitive. /Chemical
Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": Rooms
in which obvious contamination has occurred, such as spillage, should be
decontaminated by lab personnel engaged in expt. Design of expt should ... avoid
contamination of permanent equipment. ... Procedures should ensure that
maintenance workers are not exposed to carcinogens. ... Particular care should
be taken to avoid contamination of drains or ventilation ducts. In cleaning
labs, procedures should be used which do not produce aerosols or dispersal of
dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate
filter on exhaust, which are avail commercially, should be used. Sweeping,
brushing & use of dry dusters or mops should be prohibited. Grossly
contaminated cleaning materials should not be re-used ... If gowns or towels are
contaminated, they should not be sent to laundry, but ... decontaminated or
burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": Doors
leading into areas where carcinogens are used ... should be marked distinctively
with appropriate labels. Access ... limited to persons involved in expt. ... A
prominently displayed notice should give the name of the Scientific Investigator
or other person who can advise in an emergency & who can inform others (such
as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/
Non-impervious clothing which becomes wet with
liquid chloroform should be removed
promptly and not worn until the chloroform
is removed ... .
If material not involved in fire: Keep
material out of water sources and sewers. Build dikes to contain flow as
necessary.
The worker should immediately wash the skin
when it becomes contaminated.
Work clothing that becomes wet or
significantly contaminated should be removed or replaced.
Personnel protection: Keep upwind. ... Avoid
breathing vapors or dusts. Wash away any material which may have contacted the
body with copious amounts of water or soap and water.
Stability/Shelf Life:
Decomposes at ordinary temp in sunlight in the
absence of air, and in the dark in the presence of air.
... The following shelf lives were
recommended: chloroform soln and non-sedimented
mixtures could be stored in well-closed well-filled containers for 2 mo at
ambient temp; when stored in partially-filled containers periodically opened the
shelf-life should not exceed 2 wk; sedimented mixtures could be stored for 2 mo
in well-closed well-filled containers, but because loss of chloroform
could be expected in containers periodically opened such mixtures should be
prepared as required or packed in their final containers; for chloroform-containing
mixtures in the home a shelf-life of 2 wk was suggested.
Shipment Methods and Regulations:
No person may /transport,/ offer or accept a
hazardous material for transportation in commerce unless that person is
registered in conformance ... and the hazardous material is properly classed,
described, packaged, marked, labeled, and in condition for shipment as required
or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./
The International Air Transport Association (IATA)
Dangerous Goods Regulations are published by the IATA Dangerous Goods Board
pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry
carrier regulations to be followed by all IATA Member airlines when transporting
hazardous materials.
The International Maritime Dangerous Goods
Code lays down basic principles for transporting hazardous chemicals. Detailed
recommendations for individual substances and a number of recommendations for
good practice are included in the classes dealing with such substances. A
general index of technical names has also been compiled. This index should
always be consulted when attempting to locate the appropriate procedures to be
used when shipping any substance or article.
PRECAUTIONS FOR "CARCINOGENS":
Procurement ... of unduly large amt ... should be avoided. To avoid spilling,
carcinogens should be transported in securely sealed glass bottles or ampoules,
which should themselves be placed inside strong screw-cap or snap-top container
that will not open when dropped & will resist attack from the carcinogen.
Both bottle & the outside container should be appropriately labelled. ...
National post offices, railway companies, road haulage companies & airlines
have regulations governing transport of hazardous materials. These authorities
should be consulted before ... material is shipped. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": When
no regulations exist, the following procedure must be adopted. The carcinogen
should be enclosed in a securely sealed, watertight container (primary
container), which should be enclosed in a second, unbreakable, leakproof
container that will withstand chem attack from the carcinogen (secondary
container). The space between primary & secondary container should be filled
with absorbent material, which would withstand chem attack from the carcinogen
& is sufficient to absorb the entire contents of the primary container in
the event of breakage or leakage. Each secondary container should then be
enclosed in a strong outer box. The space between the secondary container &
the outer box should be filled with an appropriate quantity of shock-absorbent
material. Sender should use fastest & most secure form of transport &
notify recipient of its departure. If parcel is not received when expected,
carrier should be informed so that immediate effort can be made to find it.
Traffic schedules should be consulted to avoid ... arrival on weekend or holiday
... /Chemical Carcinogens/
Storage Conditions:
Keep in tightly closed containers; storage
code: LI
STORE IN COOL, DRY, WELL-VENTILATED LOCATION.
SEPARATE FROM STRONG ALKALIS AND STRONG MINERAL ACIDS.
Glass containers should be dark green or
amber. Technical-grade chloroform can
be stored in lead-lined or mild steel containers of all-welded construction.
When storage vessels are made of unlined steel, precautions are needed to
prevent the entry of moisture.
PVC bottles should not be used for storing or
dispensing chloroform and morphine
tincture, aqueous mixtures containing more than 5% thereof, mixtures or
dispersions in which chloroform was
present in excess of its aqueous solubility, aqueous mixtures containing chloroform
and high concn of electrolytes, or chloroform
water or mixtures containing it if the period of use would exceed six wk.
Preserve ... at a temp not exceeding 30 deg C.
PRECAUTIONS FOR "CARCINOGENS":
Storage site should be as close as practicable to lab in which carcinogens are
to be used, so that only small quantities required for ... expt need to be
carried. Carcinogens should be kept in only one section of cupboard, an
explosion-proof refrigerator or freezer (depending on chemicophysical properties
...) that bears appropriate label. An inventory ... should be kept, showing
quantity of carcinogen & date it was acquired ... Facilities for dispensing
... should be contiguous to storage area. /Chemical Carcinogens/
Cleanup Methods:
1. VENTILATE AREA OF SPILL OR LEAK. 2. COLLECT
FOR RECLAMATION OR ABSORB IN VERMICULITE, DRY SAND, EARTH, OR A SIMILAR
MATERIAL.
Flush spill area with water.
Do not touch spilled material. Use water spray
to reduce vapors. For small spills, take up with absorbent material then flush
area with water. For large spills, dike far ahead.
/SRP: In laboratory setting only:/ Absorb on
paper and evaporate on a glass dish in hood. Burn the paper. Purify /liquids/ by
distillation, then return to supplier.
PRECAUTIONS FOR "CARCINOGENS": A
high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to
minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab
hoods, glove boxes or animal rooms ... Filter housing that is designed so that
used filters can be transferred into plastic bag without contaminating
maintenance staff is avail commercially. Filters should be placed in plastic
bags immediately after removal. ... The plastic bag should be sealed
immediately. ... The sealed bag should be labelled properly ... Waste liquids
... should be placed or collected in proper containers for disposal. The lid
should be secured & the bottles properly labelled. Once filled, bottles
should be placed in plastic bag, so that outer surface ... is not contaminated.
... The plastic bag should also be sealed & labelled. ... Broken glassware
... should be decontaminated by solvent extraction, by chemical destruction, or
in specially designed incinerators. /Chemical Carcinogens/
Environmental considerations - Land spill: Dig
a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If
time permits, pits, ponds, lagoons, soak holes, or holding areas should be
sealed with an impermeable flexible membrane liner./ Dike surface flow using
soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid
with fly ash or cement powder. Apply "universal" gelling agent to
immobilize spill.
Environmental considerations - Water spill:
Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap
material at bottom. Remove trapped material with suction hoses. If dissolved, in
region of 10 ppm or greater concentration, apply activated carbon at ten times
the spilled amount. Use mechanical dredges or lifts to remove immobilized masses
of pollutants and precipitates.
Disposal Methods:
Generators of waste (equal to or greater than
100 kg/mo) containing this contaminant, EPA hazardous waste number U044, must
conform with USEPA regulations in storage, transportation, treatment and
disposal of waste.
Generators of waste (equal to or greater than
100 kg/mo) containing this contaminant, EPA hazardous waste number D022, must
conform with USEPA regulations in storage, transportation, treatment and
disposal of waste.
Group I Containers: Combustible containers
from organic or metallo-organic pesticides (except organic mercury, lead,
cadmium, or arsenic compounds) should be disposed of in pesticide incinerators
or in specified landfill sites. /Organic or metallo-organic pesticides/ product,
or to a drum reconditioner for reuse with the same type of pesticide product, if
such reuse is legal under Department of Transportation regulations (eg 49 CFR
173.28). Containers that are not to be reused should be punctured ... and
transported to a scrap metal facility for recycling, disposal or burial in a
designated landfill. /Organic or metallo-organic pesticides/
Group II Containers: Non-combustible
containers from organic or metallo-organic pesticides (except organic mercury,
lead, cadmium, or arsenic compounds) must first be triple-rinsed. Containers
that are in good condition may be returned to the manufacturer or formulator of
the pesticide product, or to a drum reconditioner for reuse with the same type
of pesticide product, if such reuse is legal under Department of Transportation
regulations (eg 49 CFR 173.28). Containers that are not to be reused should be
punctured ... and transported to a scrap metal facility for recycling, disposal
or burial in a designated landfill. /Organic or metallo-organic pesticides/
Chloroform
is a waste chemical stream constituent which may be subjected to ultimate
disposal by controlled incineration, preferably after mixing with another
combustible fuel; care must be exercised to assure complete combustion to
prevent the formation of phosgene; an acid scrubber is necessary to remove the
halo acids produced.
Potential candidate for liquid injection
incineration, with a temperature range of 650 to 1600 deg C and a residence time
of 0.1 to 2 seconds; for rotary kiln incineration with a temperature of 820 to
1600 deg C and a residence time of seconds for liquids and gases, hours for
solids; and for fluidized bed incineration, with a temperature range of 450 to
980 deg C and a residence time of seconds for liquids and gases, longer for
solids.
Peer-review: Small amt: Evaporate.
(Peer-review conclusions of an IRPTC expert consultation (May 1985))
PRECAUTIONS FOR "CARCINOGENS": There
is no universal method of disposal that has been proved satisfactory for all
carcinogenic compounds & specific methods of chem destruction ... published
have not been tested on all kinds of carcinogen-containing waste. ... Summary of
avail methods & recommendations ... /given/ must be treated as guide only.
/Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": ...
Incineration may be only feasible method for disposal of contaminated laboratory
waste from biological expt. However, not all incinerators are suitable for this
purpose. The most efficient type ... is probably the gas-fired type, in which a
first-stage combustion with a less than stoichiometric air:fuel ratio is
followed by a second stage with excess air. Some ... are designed to accept ...
aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb
soln onto suitable combustible material, such as sawdust. Alternatively, chem
destruction may be used, esp when small quantities ... are to be destroyed in
laboratory. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": HEPA
(high-efficiency particulate arrestor) filters ... can be disposed of by
incineration. For spent charcoal filters, the adsorbed material can be stripped
off at high temp & carcinogenic wastes generated by this treatment conducted
to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be
carried out by incineration at temp that ... ensure complete combustion. SOLID
WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should
be disposed of by incineration at temp high enough to ensure destruction of chem
carcinogens or their metabolites. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": ...
Small quantities of ... some carcinogens can be destroyed using chem reactions
... but no general rules can be given. ... As a general technique ... treatment
with sodium dichromate in strong sulfuric acid can be used. The time necessary
for destruction ... is seldom known ... but 1-2 days is generally considered
sufficient when freshly prepd reagent is used. ... Carcinogens that are easily
oxidizable can be destroyed with milder oxidative agents, such as saturated soln
of potassium permanganate in acetone, which appears to be a suitable agent for
destruction of hydrazines or of compounds containing isolated carbon-carbon
double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an
oxidizing agent. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS":
Carcinogens that are alkylating, arylating or acylating agents per se can be
destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl
ions, ammonia, thiols & thiosulfate. The reactivity of various alkylating
agents varies greatly ... & is also influenced by sol of agent in the
reaction medium. To facilitate the complete reaction, it is suggested that the
agents be dissolved in ethanol or similar solvents. ... No method should be
applied ... until it has been thoroughly tested for its effectiveness &
safety on material to be inactivated. For example, in case of destruction of
alkylating agents, it is possible to detect residual compounds by reaction with
4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/
The following wastewater treatment
technologies have been investigated for Chloroform:
Concentration process: Biological treatment.
The following wastewater treatment
technologies have been investigated for Chloroform:
Concentration process: stripping.
The following wastewater treatment
technologies have been investigated for Chloroform:
Concentration process: activated carbon.
The following wastewater treatment
technologies have been investigated for Chloroform:
Concentration process: resin adsorption.
SRP: At the time of review, criteria for land
treatment or burial (sanitary landfill) disposal practices are subject to
significant revision. Prior to implementing land disposal of waste residue
(including waste sludge), consult with environmental regulatory agencies for
guidance on acceptable disposal practices.
Occupational Exposure Standards:
OSHA Standards:
Permissible Exposure Limit: Table Z-1 Ceiling
value: 50 ppm (240 mg/cu m).
Vacated 1989 OSHA PEL TWA 2 ppm (9.78 mg/cu m)
is still enforced in some states.
Threshold Limit Values:
8 hr Time Weighted Avg (TWA) 10 ppm
A3. A3= Confirmed animal carcinogen with
unknown relevance to humans.
Excursion Limit Recommendation: Excursions in
worker exposure levels may exceed three times the TLV-TWA for no more than a
total of 30 min during a work day, and under no circumstances should they exceed
five times the TLV-TWA, provided that the TLV-TWA is not exceeded.
NIOSH Recommendations:
NIOSH recommends that chloroform
be regulated as a potential human carcinogen.
NIOSH usually recommends that occupational
exposures to carcinogens be limited to the lowest feasible concn.
Recommended Exposure Limit: 60 Min Short-Term
Exposure Limit: 2 ppm (9.78 mg/cu m).
Immediately Dangerous to Life or Health:
NIOSH recommends that chloroform
be regulated as a potential human carcinogen.
Other Occupational Permissible Levels:
Emergency Response Planning Guidelines (ERPG):
ERPG(1) Not appropriate; ERPG(2) 50 ppm (without serious, adverse effects) for
up to 1 hr exposure; ERPG(3) 5000 ppm (not life threatening) up to 1 hr
exposure.
Australia: 10 ppm, Category 3 carcinogen,
substances suspected of having carcinogenic potential, substance under review
(1990); Federal Republic of Germany: 10 ppm, short-term level 20 ppm, 30 min, 4
times per shift, Group B Carcinogen, justifiably suspected of having
carcinogenic potential, Pregnancy Group B, risk of damage to the developing
embryo or fetus must be considered to be probable (1990); Sweden: 2 ppm,
short-term value 5 ppm, 15 min, carcinogen (1984); United Kingdom: 10 ppm,
10-min STEL 50 ppm, substance under review (1991).
Manufacturing/Use Information:
Major Uses:
For Chloroform
(USEPA/OPP Pesticide Code: 020701) there are 0 labels match. /SRP: Not
registered for current use in the U.S., but approved pesticide uses may change
periodically and so federal, state and local authorities must be consulted for
currently approved uses./
Chloroform
is now used primarily in the manufacture of HCFC-22, monochlorodifluoromethane,
a refrigerant and as a raw material for polytetrafluoroethylene plastics.
As a solvent for fats, oils, rubber,
alkaloids, waxes, gutta-percha, resins; as cleansing agent; in fire
extinguishers to lower the freezing temp of carbon tetrachloride; in the rubber
industry.
REGISTERED FOR USE IN USA AS INSECTICIDAL
FUMIGANT ON STORED BARLEY, CORN, OATS, POPCORN, RICE, RYE, SORGHUM & WHEAT
/SRP: FORMERLY REGISTERED/
CHEM INT FOR FLUOROCARBON 22
(CHLORODIFLUOROMETHANE)
EXTRACTION & PURIFICATION SOLVENT - EG,
FOR PENICILLIN
MILDEWCIDE FOR TOBACCO SEEDLINGS
DRY CLEANING AGENT
CHEM INT FOR DYES & PESTICIDES
POLYMER CHAIN TRANSFER AGENT
CHEM INT FOR TRIBROMOMETHANE
MEDICATION (VET):
Has been used as an anesthetic and in
pharmaceutical preparations.
COMPONENT OF COUGH SYRUPS, TOOTHPASTES (FORMER
USE)
COMPONENT OF LINAMENTS & TOOTHACHE CMPD
(FORMER USE)
As a solvent for coating compositions of urea
or melamine resins and for preparations of lubricant additives and plasticizers;
surface-active agents; lubricant additives, rubber chemicals, flotation agents,
antifoam agent; flavoring agent; reaction medium for hydrogen pyroxide
production; defoamer.
Manufacturers:
Dow Chemical USA, Hq,Dow Center, Midland, MI
48674, (517) 636-1000; Production site: Freeport, TX 77541; Production site:
Plaquemine, LA 70765
Vulcan Materials Company, Vulcan Chemicals
Group, P.O. Box 530390, Birmingham, AL 35253-0390, (205)877-3000. Chloralkali
Business Unit; Production sites: Giesmar LA 70734; Wichita, KS 67277
Methods of Manufacturing:
Made from acetone and bleaching powder by addn
of sulfuric acid. May also be prepared by carefully controlled chlorination of
methane.
Today, trichloromethane
(chloroform) is prepared exclusively
and on a massive scale by the chlorination of methane and/or monochloromethane.
Reaction of chlorinated lime with acetone,
acetaldehyde, or ethanol. By-product from the chlorination of methane.
Hypochlorite reacts with aldehyde to produce chloroform.
General Manufacturing Information:
Method of purification: extraction with
concentrated sulfuric acid and rectification.
HCFC-22 (produced using chloroform)
has an ODP(ozone depletion potential) that is about 1/10 that of CFC-11 and
CFC-12, but it and other HCFCs are considered interim products along the way to
non-chlorine-containing HFCs. HCFC-22 use is expected to be curtailed by 2010 in
the US, although environmentalists are pushing for an earlier phaseout date and
proposals in other countries are calling for restrictions on the material's
uses. Under the Montreal Protocol, HCFC-22 is scheduled to be phased out
globally by the year 2030.
Small quantities of ethyl alcohol stablilize chloroform
during storage.
Noncommercial processes include limited
reduction of carbon tetrachloride to chloroform,
effected by reaction with hydrogen, methane, zinc dust, or ethyl alcohol;
decomposition of pentachloroethane with aluminum chloride; electrolysis of
alkali-metal or alkaline-earth metal chlorides in aqueous alcohol solution; or
monoxide and hydrogen chloride under pressure at about 40 deg C in the presence
of catalytic oxides
Formulations/Preparations:
Grade: Technical, CP, ACS, NF, reagent
Very high purity grades; AR, NANOGRADE,
ChromAR, SpectrAR, HPLC grades
At least one grain fumigant mixture contains chloroform
(73.2%) with carbon disulfide (26.8%).
Chloroform
emulsion: chloroform 5 ml, quillaia
liquid extract 0.1 ml, tragacanth mucilage 5 ml, water to 100 ml
Chloroform
spirit: chloroform 5% vol/vol in
alcohol (90%)
Chloroform
water: chloroform 0.25% vol/vol in
freshly boiled and cooled water
Concentrated chloroform
water: chloroform 10 ml, alcohol (90%)
60 ml, water to 100 ml
Double-strength chloroform
water: chloroform 0.5% vol/vol in
freshly boiled and cooled water
Chloroform
and morphine tincture: chloroform 12.5
ml, morphine hydrochloride 229 mg, alcohol (90%) 12.5 ml, liquorice liquid
extract 12.5 ml, treacle of commerce 12.5 ml, water 5 ml, anesthetic ether 3 ml,
peppermint oil 0.1 ml, syrup to 100 ml.
Chloroform
contains not less than 99.0% and not more than 99.5% chloroform,
the remainder consisting of alcohol.
Impurities:
Reagent grade chloroform
of several brands was reported to contain detectable amounts of methylene
chloride and other chloromethanes.
Typical specifications for National Formulary
grade chloroform ... acidity, as
hydrogen chloride, 0.0002% max; residue on evaporation, 0.0013% max; and
stabilizer, 0.5 to 1.0% ethanol by volume. Technical grade chloroform
... acidity, as hydrogen chloride, 0.002% max; residue on evaporation, 0.0007%
max; moisture, 0.0150% max; and stabilizer, 0.5 to 1.0% ethanol by volume.
The following impurities have been detected in
chloroform: bromochloromethane,
bromodichloroethane, bromodichloromethane, carbon tetrachloride,
dibromodichloroethane, dibromodichloromethane, 1,1-dichloroethane,
1,2-dichloroethane, vinylidene chloride, cis-1,2-dichloroethene,
trans-1,2-dichloroethylene, dichloromethane, diethyl carbonate, ethyl benzene,
2-methoxy ethanol, nitromethane, pyridine, 1,1,2,2-tetrachloroethane,
trichloroethylene, meta-xylene, ortho-xylene, and para-xylene.
n-Nitrosomorpholine was found in 4/10 batches
of analytical grade chloroform, at
levels of 2-376 ug/l.
A representative technical quality chloroform
contains the following amounts of the indicated substances (maximums): Water (50
ppm), acid as HCL (10 ppm), methylene chloride (200 ppm), bromochloromethane
(300 ppm), carbon tetrachloride (250 ppm), 1,2-dichloroethylene (100 ppm),
vinylidene chloride (100 ppm), residue on evaporation at 110 deg C (10 ppm), and
dissolved chlorine (not detectable).
Consumption Patterns:
CHEM INT FOR FLUOROCARBON 22, 96%; OTHER, 4%
(1981)
Fluorocarbon 22, 93% (refrigerants, 70%;
fluoropolymers, 30%); miscellaneous, 4%; export, 3% (1986)
CHEMICAL PROFILE: Chloroform.
Fluorocarbon 22, 90% (refrigerants, 70%; fluoropolymers, 30%); export, 8%;
other, 2%
CHEMICAL PROFILE: Chloroform.
Demand: 1988: 500 million lb; 1989: 525 million lb; 1993 /projected/: 650
million lb (Includes exports, but not imports, which totaled 24 million lb last
year).
Hydrochlorofluorocarbon 22 (HCFC-22), 98%
(refrigerants 70%; fluoropolymers 30%); miscellaneous, including laboratory
reagents and extraction solvents for pharmaceuticals, 2%.
U. S. Production:
(1981) 1.82X10+11 G
(1982) 402 million lb
(1978) 1.58X10+11 G
(1983) 1.68X10+11 G
(1977): 93 million to 350 million lb (includes
importation)
(1985) 1.25X10+11 g
(1986) 4.21X10+8 lb
(1988) 5.23X10+8 lb
(1987) 4.61X10+8 lb
(1989) 266.53X10+3 tons
(1990) 219,687,000 kg
(1991) 228,901,000 kg
(1993) 215,932,000 kg
U. S. Imports:
(1985) 1.52X10+10 g
U. S. Exports:
(1985) 1.99X10+10 g
Laboratory Methods:
Clinical Laboratory Methods:
Headspace analysis of chloroform
in blood uses gas chromatography and flame ionization detection. Retention time
is 2.0 min. This method has a sensitivity of 0.1 mg/l. Normal plasma components
do not interfere with the assay, but many other volatile organic cmpd are
detected with this technique and may interfere.
FISH SAMPLES WERE ANALYZED FOR CHLOROFORM
BY GAS CHROMATOGRAPHY. DETECTION LIMIT IS IN 0.1-1.0 PPB RANGE.
Analytic Laboratory Methods:
EPA Method 624: Purgeables. A purge-and-trap
gas chromatography/mass spectrometry method for the analysis of Chloroform
in municipal and industrial discharges, consists of a glass column, 6 ft x 0.1
in, packed with Carbopack B (60/80 mesh) coated with 1% SP-1000, with the
detection performed by the mass spectrometer, and helium as the carrier gas at a
flow rate of 30 ml/min. A sample injection volume of 2 to 5 ul is suggested, the
column temperature is held isothermal at 45 deg C for 3 min and then programmed
at 8 deg C/min to a final temperature of 220 deg C. This method has a detection
limit of 1.6 ug/l and an overall precision of 0.18 times the average recovery +
0.16, over a working range of 5 to 600 ug/l.
Chloroform,
as a volatile fumigant in wheat and corn grain, is analyzed using gas
chromatography equipped with source-heated electron capture detection. Retention
time for chloroform is 3 min.
Chloroform
in drugs using titrimetric method. The sample is acidified with nitric acid and
mixed with silver nitrate. Iron ammonium sulfate is added as an indicator, and
excess silver nitrate is titrated using 0.05 N ammonium or potassium
thiocyanate. Each ml 0.1N silver nitrate = 0.00398 g chloroform.
Chloroform
in drugs using infrared spectrophotometry and standard curves determined after
extracting sample with carbon disulfide. Peak infrared absorption is at 8.25 um
with a baseline of 7.70 to 8.70 um.
AOAC Method 977.18. Volatile Fumigants in
Grain by Gas Chromatographic Method.
EPA Method 601: Purgeable Halocarbons. A
purge-and-trap gas chromatography method for the analysis of chloroform
in municipal and industrial discharges, consists of a stainless steel column, 8
ft x 0.1 in ID, packed with Carbopack B (60/80 mesh) coated with SP-1000, with
electrolytic conductivity detection, and helium as the carrier gas at a flow
rate of 40 ml/min. A sample injection volume of 2 to 5 ul is suggested, the
column temperature is held isothermal at 45 deg C for 3 min then programmed at 8
deg C/min to final temperature of 220 deg C. This method has a detection limit
of 0.05 ug/l and an overall precision of 0.19 times the average recovery - 0.02,
over a working range of 8.0 to 500 ug/l.
The most widely used method of analysis for chloroform
is gas chromatography. The detector of choice is a flame ionization detector. Chloroform
may be estimated quantitatively by determining the amount of copper oxide
produced when it is warmed with Fehling's solution, which is potassium
cupritartrate. An alternative procedure consists of heating the chloroform
with concentrated alcoholic potassium hydroxide in a sealed tube at 100 deg C
and determining the amount of potassium chloride produced.
AOB Method VA-004-1. Halogenated Volatile
Organic Compounds (VOCs) in Air by direct Gas Chromatography with an Electron
Capture Detector.
AOB Method VA-006-1. Volatile Organic
Compounds (VOCs) in Ambient Air by Direct Portable GC/PID.
NIOSH Method 1003. Determination of
Halogenated Hydrocarbons by Gas Chromatography with Flame Ionization Detection.
EPA Method EMSLC 551. Determination of
Chlorination Disinfection Byproducts and Chlorinated Solvents in Drinking Water
by Liquid-Liquid Extraction and Gas Chromatography with Electron-Capture
Detection.
Sampling Procedures:
NIOSH 1003: Analyte: Chloroform;
Matrix: Air; Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg);
Flow rate: 0.01-0.2 l/min; Vol: min 1 l @ 50 ppm, max 50 l; Stability: not
determined /Hydrocarbons, halogenated/
Special References:
Special Reports:
REUBER MD; CARCINOGENICITY OF CHLOROFORM;
ENVIRON HEALTH PERSPECT 31: 171-82 (1979). A REVIEW ARTICLE ON CARCINOGENICITY
OF CHLOROFORM.
USEPA; Locating and Estimating Air Emissions
from Sources of Chloroform (1984) EPA
450/4-84-007c
USEPA; Ambient Water Quality Criteria Doc: Chloroform
(1980) EPA 440/5-80-033
USEPA; Health Assessment Document: Chloroform
(Draft) (1984) EPA-600/8-84-004A
DHHS/ATSDR; Toxicological Profile for Chloroform
(Update) TP-92/07 (1993)
USEPA; Health and Environmental Effects
Profile for Chloroform (Carbon
Trichloromethone); No 47 (1980)
WHO; Environmental Health Criteria 119:
Principles and Methods for the Assessment of Nephrotoxicity Associated with
Exposure to Chemicals (1991)
U.S. Department of Health & Human
Services/National Toxicology Program; Tenth Report on Carcinogens. National
Institutes of Environmental Health Sciences. The Report on Carcinogens is an
informational scientific and public health document that identifies and
discusses substances (including agents, mixtures, or exposure circumstances)
that may pose a carcinogenic hazard to human health. Chloroform
(67-66-3) was first listed in the Second Annual Report on Carcinogens (1981) as
reasonably anticipated to be a human carcinogen.
Synonyms and Identifiers:
Synonyms:
R 20
**PEER REVIEWED**
CHLOROFORME (FRENCH)
**PEER REVIEWED**
CLOROFORMIO
(ITALIAN)
**PEER REVIEWED**
Pesticide Code: 020701
**QC REVIEWED**
FORMYL TRICHLORIDE
**PEER REVIEWED**
Freon 20
**PEER REVIEWED**
METHANE TRICHLORIDE
**PEER REVIEWED**
METHANE, TRICHLORO-
**PEER REVIEWED**
METHENYL CHLORIDE
**PEER REVIEWED**
METHENYL TRICHLORIDE
**PEER REVIEWED**
METHYL TRICHLORIDE
**PEER REVIEWED**
NCI-C02686
**PEER REVIEWED**
R 20 (REFRIGERANT)
**PEER REVIEWED**
TCM
**PEER REVIEWED**
TRICHLOORMETHAAN
(DUTCH)
**PEER REVIEWED**
TRICHLORMETHAN
(CZECH)
**PEER REVIEWED**
TRICHLOROFORM
**PEER REVIEWED**
TRICHLOROMETHANE
**PEER REVIEWED**
TRICLOROMETANO
(ITALIAN)
**PEER REVIEWED**
Formulations/Preparations:
Grade: Technical, CP, ACS, NF, reagent
Very high purity grades; AR, NANOGRADE,
ChromAR, SpectrAR, HPLC grades
At least one grain fumigant mixture contains chloroform
(73.2%) with carbon disulfide (26.8%).
Chloroform
emulsion: chloroform 5 ml, quillaia
liquid extract 0.1 ml, tragacanth mucilage 5 ml, water to 100 ml
Chloroform
spirit: chloroform 5% vol/vol in
alcohol (90%)
Chloroform
water: chloroform 0.25% vol/vol in
freshly boiled and cooled water
Concentrated chloroform
water: chloroform 10 ml, alcohol (90%)
60 ml, water to 100 ml
Double-strength chloroform
water: chloroform 0.5% vol/vol in
freshly boiled and cooled water
Chloroform
and morphine tincture: chloroform 12.5
ml, morphine hydrochloride 229 mg, alcohol (90%) 12.5 ml, liquorice liquid
extract 12.5 ml, treacle of commerce 12.5 ml, water 5 ml, anesthetic ether 3 ml,
peppermint oil 0.1 ml, syrup to 100 ml.
Chloroform
contains not less than 99.0% and not more than 99.5% chloroform,
the remainder consisting of alcohol.
Shipping Name/ Number DOT/UN/NA/IMO:
UN 1888; Chloroform
IMO 6.1; Chloroform
Standard Transportation Number:
49 403 10; Chloroform
(not elsewhere classified, other than technical grade)
49 403 11; Chloroform
(not elsewhere classified, technical grade)
EPA Hazardous Waste Number:
U044; A toxic waste when a discarded
commercial chemical product or manufacturing chemical intermediate or an
off-specification commercial chemical product or manufacturing chemical
intermediate.
Administrative Information:
Hazardous Substances Databank Number:
56
Last Revision Date: 20030829
Last Review Date: Reviewed by
SRP on 1/29/2000
Update History:
Complete Update on 2003-08-29, 1 fields
added/edited/deleted
Complete Update on 03/05/2003, 5 fields added/edited/deleted.
Field Update on 02/14/2003, 1 field added/edited/deleted.
Field Update on 11/08/2002, 1 field added/edited/deleted.
Field Update on 10/31/2002, 1 field added/edited/deleted.
Complete Update on 05/31/2002, 1 field added/edited/deleted.
Complete Update on 05/13/2002, 1 field added/edited/deleted.
Complete Update on 01/18/2002, 2 fields added/edited/deleted.
Field Update on 01/14/2002, 1 field added/edited/deleted.
Complete Update on 08/09/2001, 1 field added/edited/deleted.
Complete Update on 05/16/2001, 1 field added/edited/deleted.
Complete Update on 02/20/2001, 2 fields added/edited/deleted.
Complete Update on 01/30/2001, 1 field added/edited/deleted.
Complete Update on 11/08/2000, 1 field added/edited/deleted.
Complete Update on 06/08/2000, 81 fields added/edited/deleted.
Field Update on 02/02/2000, 1 field added/edited/deleted.
Field Update on 11/29/1999, 1 field added/edited/deleted.
Field Update on 09/21/1999, 1 field added/edited/deleted.
Field Update on 08/26/1999, 1 field added/edited/deleted.
Complete Update on 05/04/1999, 1 field added/edited/deleted.
Complete Update on 03/29/1999, 3 fields added/edited/deleted.
Field Update on 03/19/1999, 1 field added/edited/deleted.
Field Update on 03/17/1999, 1 field added/edited/deleted.
Complete Update on 03/01/1999, 1 field added/edited/deleted.
Complete Update on 02/01/1999, 1 field added/edited/deleted.
Complete Update on 01/20/1999, 1 field added/edited/deleted.
Complete Update on 11/12/1998, 1 field added/edited/deleted.
Complete Update on 10/07/1998, 1 field added/edited/deleted.
Complete Update on 06/02/1998, 1 field added/edited/deleted.
Complete Update on 02/25/1998, 1 field added/edited/deleted.
Complete Update on 03/27/1997, 2 fields added/edited/deleted.
Complete Update on 03/11/1997, 3 fields added/edited/deleted.
Complete Update on 02/24/1997, 1 field added/edited/deleted.
Complete Update on 07/22/1996, 4 fields added/edited/deleted.
Complete Update on 05/03/1996, 2 fields added/edited/deleted.
Complete Update on 04/16/1996, 9 fields added/edited/deleted.
Field Update on 01/18/1996, 1 field added/edited/deleted.
Complete Update on 11/10/1995, 1 field added/edited/deleted.
Complete Update on 02/13/1995, 1 field added/edited/deleted.
Complete Update on 01/18/1995, 1 field added/edited/deleted.
Complete Update on 12/19/1994, 1 field added/edited/deleted.
Complete Update on 09/26/1994, 1 field added/edited/deleted.
Complete Update on 08/31/1994, 2 fields added/edited/deleted.
Complete Update on 08/23/1994, 1 field added/edited/deleted.
Complete Update on 07/20/1994, 1 field added/edited/deleted.
Complete Update on 05/05/1994, 1 field added/edited/deleted.
Complete Update on 03/25/1994, 1 field added/edited/deleted.
Complete Update on 02/02/1994, 1 field added/edited/deleted.
Complete Update on 11/05/1993, 1 field added/edited/deleted.
Complete Update on 08/07/1993, 1 field added/edited/deleted.
Complete Update on 08/04/1993, 1 field added/edited/deleted.
Field update on 12/10/1992, 1 field added/edited/deleted.
Complete Update on 04/01/1992, 1 field added/edited/deleted.
Complete Update on 01/23/1992, 1 field added/edited/deleted.
Complete Update on 05/08/1991, 1 field added/edited/deleted.
Complete Update on 05/07/1991, 1 field added/edited/deleted.
Complete Update on 02/13/1991, 72 fields added/edited/deleted.
Field Update on 08/23/1990, 1 field added/edited/deleted.
Field Update on 05/04/1990, 1 field added/edited/deleted.
Complete Update on 01/11/1990, 62 fields added/edited/deleted.
Field Update on 05/05/1989, 1 field added/edited/deleted.
Field Update on 03/01/1989, 1 field added/edited/deleted.
Field Update on 05/12/1988, 1 fields added/edited/deleted.
Complete Update on 03/04/1988, 115 fields added/edited/deleted.
Complete Update on 05/02/1985
Created 19830315 by DS
GLCC RELATED TOXIC SUBSTANCES
FOUND IN THE CAMP POND
AND CAMP WATER WELL
2003 AND 2004
GREAT LAKES CHEMICAL CORPORATION AND THE PATHFINDERS CAMP